Patrice Wendling

CHICAGO – Long-term therapy with monthly zoledronic acid provides sustained survival benefits over daily oral bisphosphonates in multiple myeloma, with no evidence of a cumulative increase in the risk of osteonecrosis of the jaw.

After a median follow-up of 5.8 years in the MRC (U.K. Medical Research Council) Myeloma IX trial, zoledronic acid (Zometa) significantly improved the primary end points of progression-free survival (19 months vs. 18 months; hazard ratio, 0.88; P = .01) and overall survival (51 months vs. 46 months; HR, 0.88; P = .03) compared with oral clodronate. Patients in both arms of the trial received first-line intensive or nonintensive chemotherapy.

The overall cumulative incidence of osteonecrosis of the jaw (ONJ) was low, at 3.7% for zoledronic acid and 0.5% for clodronate (P less than .0001), Dr. Gareth J. Morgan reported at the annual meeting of the American Society of Clinical Oncology. ONJ is one of the most common reasons for discontinuing bisphosphonates, with previous reports’ linking the duration of exposure to its development.

"The first cases tend to occur by 12 months. These plateaued by about 36 months, and from that time on there is no continued cases or accrual of new cases," said Dr. Morgan, professor of hematology and head of the myeloma unit at Royal Marsden Hospital, London.

Session moderator Dr. Rafat Abonour, professor of medicine and director of adult clinical research in the cancer center at Indiana University, Indianapolis, said in an interview that IV bisphosphonates seem to be superior to oral ones, with less skeletal-related events and better survival.

"Survival is impressive," he said. "[The] low rate of ONJ is assuring that the benefit-risk ratio is in favor of using zoledronic acid."

The MRC Myeloma IX trial investigators previously reported significant progression-free and overall survival benefits for zoledronic acid over clodronate at 3.7 years’ follow-up (Lancet 2010;376:1965-6). They also found that zoledronic acid significantly reduces the risk of skeletal-related events, even among patients without bone lesions at baseline – a subset generally not considered for bisphosphonate therapy (Lancet Oncol. 2011;12:743-52).

Bisphosphonates such as zoledronic acid inhibit osteoclast-mediated osteolysis, and are used along with chemotherapy to treat bone lesions present in about 70% of patients at diagnosis of multiple myeloma. The optimal duration of use, however, has not been determined.

The current data provide the longest follow-up from the MRC Myeloma IX trial, and further evidence that zoledronic acid also exerts an antimyeloma effect, said Dr. Morgan.

Investigators at 120 centers in the United Kingdom randomly assigned 1,960 patients with newly diagnosed stage I-III multiple myeloma to intravenous zoledronic acid at 4 mg every 21-28 days or oral 1,600 mg clodronate daily plus nonintensive chemotherapy consisting of oral melphalan and prednisone (MP) or attenuated oral cyclophosphamide, thalidomide and dexamethasone (C-TDa), or intensive chemotherapy consisting of cyclophosphamide, vincristine, doxorubicin and dexamethasone (CVAD) or C-TD. After first-line treatment, patients were randomly assigned to maintenance therapy with thalidomide at 50 mg/day initially, increasing to 100 mg/day if tolerated, or to no thalidomide maintenance.

Renal failure rates ranged from 5% to 7% in the zoledronic group and from 6% to 7% in the clodronate group. ONJ rates ranged from 2% to 5% among zoledronate patients, compared with 0 to 1% for those who were given clodronate.

The study found that concomitant use of thalidomide seemed to reduce the rate of ONJ, Dr. Morgan noted. "This may reflect part of the mechanism of how ONJ occurs or it may relate to the fact that the responses are greater in the thalidomide-treated group," he added.

Among intensively treated zoledronic acid patients, ONJ rates fell significantly from 4.7% with CVAD to 3.2% with cyclophosphamide, thalidomide and dexamethasone (C-TD) chemotherapy. In the clodronate group, rates fell from 1.1% to 0%.

The same was true for nonintensively treated zoledronic acid patients, with ONJ rates decreasing significantly from 4.7% with melphalan and prednisone to 1.9% with attenuated C-TD, Dr. Morgan said. Rates for clodronate patients were 0.5% for both chemotherapy regimens.

Of note, thalidomide is used less in the United States. Furthermore, most U.S. oncologists use zoledronic acid and pamidronate (Aredia) rather than clodronate in the management of these patients.

Among nine zoledronic acid patients and one clodronate patient with ONJ recovery data, four had complete recovery, two improved, and four had no change, he said. Dental surgery or trauma preceded ONJ in six zoledronic patients.

The low ONJ incidence in the trial is likely due to the ONJ recommendations (Crit. Rev. Oncol. Hematol. 2007;62:148-152) that were disseminated to Myeloma IX investigators in June 2006, Dr. Morgan observed.

To reduce ONJ rates even further, he recommends that all patients receive a comprehensive dental examination before using bisphosphonates. Any unsalvageable teeth should be removed, all invasive dental procedures completed, and optimal periodontal health achieved.

The U.K. MRC funded the trial. Dr. Morgan reported honoraria and other relationships with Celgene, Johnson & Johnson, Merck, Novartis, and other companies. Dr. Abonour reported no conflicts of interest.

CHICAGO – Long-term therapy with monthly zoledronic acid provides sustained survival benefits over daily oral bisphosphonates in multiple myeloma, with no evidence of a cumulative increase in the risk of osteonecrosis of the jaw.

After a median follow-up of 5.8 years in the MRC (U.K. Medical Research Council) Myeloma IX trial, zoledronic acid (Zometa) significantly improved the primary end points of progression-free survival (19 months vs. 18 months; hazard ratio, 0.88; P = .01) and overall survival (51 months vs. 46 months; HR, 0.88; P = .03) compared with oral clodronate. Patients in both arms of the trial received first-line intensive or nonintensive chemotherapy.

The overall cumulative incidence of osteonecrosis of the jaw (ONJ) was low, at 3.7% for zoledronic acid and 0.5% for clodronate (P less than .0001), Dr. Gareth J. Morgan reported at the annual meeting of the American Society of Clinical Oncology. ONJ is one of the most common reasons for discontinuing bisphosphonates, with previous reports’ linking the duration of exposure to its development.

"The first cases tend to occur by 12 months. These plateaued by about 36 months, and from that time on there is no continued cases or accrual of new cases," said Dr. Morgan, professor of hematology and head of the myeloma unit at Royal Marsden Hospital, London.

Session moderator Dr. Rafat Abonour, professor of medicine and director of adult clinical research in the cancer center at Indiana University, Indianapolis, said in an interview that IV bisphosphonates seem to be superior to oral ones, with less skeletal-related events and better survival.

"Survival is impressive," he said. "[The] low rate of ONJ is assuring that the benefit-risk ratio is in favor of using zoledronic acid."

The MRC Myeloma IX trial investigators previously reported significant progression-free and overall survival benefits for zoledronic acid over clodronate at 3.7 years’ follow-up (Lancet 2010;376:1965-6). They also found that zoledronic acid significantly reduces the risk of skeletal-related events, even among patients without bone lesions at baseline – a subset generally not considered for bisphosphonate therapy (Lancet Oncol. 2011;12:743-52).

Bisphosphonates such as zoledronic acid inhibit osteoclast-mediated osteolysis, and are used along with chemotherapy to treat bone lesions present in about 70% of patients at diagnosis of multiple myeloma. The optimal duration of use, however, has not been determined.

The current data provide the longest follow-up from the MRC Myeloma IX trial, and further evidence that zoledronic acid also exerts an antimyeloma effect, said Dr. Morgan.

Investigators at 120 centers in the United Kingdom randomly assigned 1,960 patients with newly diagnosed stage I-III multiple myeloma to intravenous zoledronic acid at 4 mg every 21-28 days or oral 1,600 mg clodronate daily plus nonintensive chemotherapy consisting of oral melphalan and prednisone (MP) or attenuated oral cyclophosphamide, thalidomide and dexamethasone (C-TDa), or intensive chemotherapy consisting of cyclophosphamide, vincristine, doxorubicin and dexamethasone (CVAD) or C-TD. After first-line treatment, patients were randomly assigned to maintenance therapy with thalidomide at 50 mg/day initially, increasing to 100 mg/day if tolerated, or to no thalidomide maintenance.

Renal failure rates ranged from 5% to 7% in the zoledronic group and from 6% to 7% in the clodronate group. ONJ rates ranged from 2% to 5% among zoledronate patients, compared with 0 to 1% for those who were given clodronate.

The study found that concomitant use of thalidomide seemed to reduce the rate of ONJ, Dr. Morgan noted. "This may reflect part of the mechanism of how ONJ occurs or it may relate to the fact that the responses are greater in the thalidomide-treated group," he added.

Among intensively treated zoledronic acid patients, ONJ rates fell significantly from 4.7% with CVAD to 3.2% with cyclophosphamide, thalidomide and dexamethasone (C-TD) chemotherapy. In the clodronate group, rates fell from 1.1% to 0%.

The same was true for nonintensively treated zoledronic acid patients, with ONJ rates decreasing significantly from 4.7% with melphalan and prednisone to 1.9% with attenuated C-TD, Dr. Morgan said. Rates for clodronate patients were 0.5% for both chemotherapy regimens.

Of note, thalidomide is used less in the United States. Furthermore, most U.S. oncologists use zoledronic acid and pamidronate (Aredia) rather than clodronate in the management of these patients.

Among nine zoledronic acid patients and one clodronate patient with ONJ recovery data, four had complete recovery, two improved, and four had no change, he said. Dental surgery or trauma preceded ONJ in six zoledronic patients.

The low ONJ incidence in the trial is likely due to the ONJ recommendations (Crit. Rev. Oncol. Hematol. 2007;62:148-152) that were disseminated to Myeloma IX investigators in June 2006, Dr. Morgan observed.

To reduce ONJ rates even further, he recommends that all patients receive a comprehensive dental examination before using bisphosphonates. Any unsalvageable teeth should be removed, all invasive dental procedures completed, and optimal periodontal health achieved.

The U.K. MRC funded the trial. Dr. Morgan reported honoraria and other relationships with Celgene, Johnson & Johnson, Merck, Novartis, and other companies. Dr. Abonour reported no conflicts of interest.

CHICAGO – Long-term therapy with monthly zoledronic acid provides sustained survival benefits over daily oral bisphosphonates in multiple myeloma, with no evidence of a cumulative increase in the risk of osteonecrosis of the jaw.

After a median follow-up of 5.8 years in the MRC (U.K. Medical Research Council) Myeloma IX trial, zoledronic acid (Zometa) significantly improved the primary end points of progression-free survival (19 months vs. 18 months; hazard ratio, 0.88; P = .01) and overall survival (51 months vs. 46 months; HR, 0.88; P = .03) compared with oral clodronate. Patients in both arms of the trial received first-line intensive or nonintensive chemotherapy.

The overall cumulative incidence of osteonecrosis of the jaw (ONJ) was low, at 3.7% for zoledronic acid and 0.5% for clodronate (P less than .0001), Dr. Gareth J. Morgan reported at the annual meeting of the American Society of Clinical Oncology. ONJ is one of the most common reasons for discontinuing bisphosphonates, with previous reports’ linking the duration of exposure to its development.

"The first cases tend to occur by 12 months. These plateaued by about 36 months, and from that time on there is no continued cases or accrual of new cases," said Dr. Morgan, professor of hematology and head of the myeloma unit at Royal Marsden Hospital, London.

Session moderator Dr. Rafat Abonour, professor of medicine and director of adult clinical research in the cancer center at Indiana University, Indianapolis, said in an interview that IV bisphosphonates seem to be superior to oral ones, with less skeletal-related events and better survival.

"Survival is impressive," he said. "[The] low rate of ONJ is assuring that the benefit-risk ratio is in favor of using zoledronic acid."

The MRC Myeloma IX trial investigators previously reported significant progression-free and overall survival benefits for zoledronic acid over clodronate at 3.7 years’ follow-up (Lancet 2010;376:1965-6). They also found that zoledronic acid significantly reduces the risk of skeletal-related events, even among patients without bone lesions at baseline – a subset generally not considered for bisphosphonate therapy (Lancet Oncol. 2011;12:743-52).

Bisphosphonates such as zoledronic acid inhibit osteoclast-mediated osteolysis, and are used along with chemotherapy to treat bone lesions present in about 70% of patients at diagnosis of multiple myeloma. The optimal duration of use, however, has not been determined.

The current data provide the longest follow-up from the MRC Myeloma IX trial, and further evidence that zoledronic acid also exerts an antimyeloma effect, said Dr. Morgan.

Investigators at 120 centers in the United Kingdom randomly assigned 1,960 patients with newly diagnosed stage I-III multiple myeloma to intravenous zoledronic acid at 4 mg every 21-28 days or oral 1,600 mg clodronate daily plus nonintensive chemotherapy consisting of oral melphalan and prednisone (MP) or attenuated oral cyclophosphamide, thalidomide and dexamethasone (C-TDa), or intensive chemotherapy consisting of cyclophosphamide, vincristine, doxorubicin and dexamethasone (CVAD) or C-TD. After first-line treatment, patients were randomly assigned to maintenance therapy with thalidomide at 50 mg/day initially, increasing to 100 mg/day if tolerated, or to no thalidomide maintenance.

Renal failure rates ranged from 5% to 7% in the zoledronic group and from 6% to 7% in the clodronate group. ONJ rates ranged from 2% to 5% among zoledronate patients, compared with 0 to 1% for those who were given clodronate.

The study found that concomitant use of thalidomide seemed to reduce the rate of ONJ, Dr. Morgan noted. "This may reflect part of the mechanism of how ONJ occurs or it may relate to the fact that the responses are greater in the thalidomide-treated group," he added.

Among intensively treated zoledronic acid patients, ONJ rates fell significantly from 4.7% with CVAD to 3.2% with cyclophosphamide, thalidomide and dexamethasone (C-TD) chemotherapy. In the clodronate group, rates fell from 1.1% to 0%.

The same was true for nonintensively treated zoledronic acid patients, with ONJ rates decreasing significantly from 4.7% with melphalan and prednisone to 1.9% with attenuated C-TD, Dr. Morgan said. Rates for clodronate patients were 0.5% for both chemotherapy regimens.

Of note, thalidomide is used less in the United States. Furthermore, most U.S. oncologists use zoledronic acid and pamidronate (Aredia) rather than clodronate in the management of these patients.

Among nine zoledronic acid patients and one clodronate patient with ONJ recovery data, four had complete recovery, two improved, and four had no change, he said. Dental surgery or trauma preceded ONJ in six zoledronic patients.

The low ONJ incidence in the trial is likely due to the ONJ recommendations (Crit. Rev. Oncol. Hematol. 2007;62:148-152) that were disseminated to Myeloma IX investigators in June 2006, Dr. Morgan observed.

To reduce ONJ rates even further, he recommends that all patients receive a comprehensive dental examination before using bisphosphonates. Any unsalvageable teeth should be removed, all invasive dental procedures completed, and optimal periodontal health achieved.

The U.K. MRC funded the trial. Dr. Morgan reported honoraria and other relationships with Celgene, Johnson & Johnson, Merck, Novartis, and other companies. Dr. Abonour reported no conflicts of interest.

MINNEAPOLIS – Increased levels of the stress biomarker alpha-amylase, but not cortisol, are significantly associated with a lower chance of conception, a couple-based, prospective study has shown.

The odds of pregnancy were slashed 31% for women whose salivary levels of alpha-amylase were in the highest tertile, compared with women whose levels were in the lowest tertile after adjustment for such important confounders as the difference between partners’ ages, intercourse during the fertile window and the woman’s age, income, race, parity, smoking, caffeine intake, and alcohol use (odds ratio, 0.69).

Patrice Wendling/IMNG Medical Media

This study is the first in the United States to prospectively examine the association between physiologic stress and fecundity among couples trying to conceive, lead author Courtney D. Lynch, Ph.D., said at the annual meeting of the Society for Pediatric and Perinatal Epidemiologic Research.

"We previously published similar results in a population in the U.K., and we were quite astounded that we found exactly the same thing," she said.

In that study (Fertil. Steril. 2011;95:2184-9), alpha-amylase was negatively associated with fecundity in the first cycle of attempting pregnancy (OR, 0.85) after adjustment for the couples’ age, intercourse frequency during the fertile window, and female alcohol use.

The current analysis was based on 501 couples in Michigan and Texas who were attempting pregnancy and were followed for up to 12 months and then through pregnancy, if pregnancy occurred, as part of the LIFE (Longitudinal Investigation of Fertility and the Environment) study. Cortisol and alpha-amylase concentrations were determined by enzyme immunoassay from salivary samples collected by the women on the day following enrollment and the day following the start of their first menses in the study.

The women, aged 18-40 years, were mostly white (78%), college graduates (75%), and nonsmokers (73%). Their mean age was 30 years, 53% were nulliparous, and 55% were overweight or obese.

Of the 401 couples who completed the protocol, 87% achieved pregnancy and 13% did not.

Complete data evaluable on 393 couples showed no significant differences between women who did or did not become pregnant in mean levels of cortisol (0.46 μg/dL vs. 0.36 μg/dL) or alpha-amylase (23.6 U/mL vs. 32.0 U/mL), said Dr. Lynch, an epidemiologist at Ohio State University in Columbus.

The adjusted odds of pregnancy were similar for women with salivary cortisol in the lowest tertile (0.02-0.30 μg/dL; OR, 1.0), middle tertile (0.31-0.42 μg/dL; OR, 0.90), or highest tertile (0.43-15.60 μg/dL; OR, 0.91).

The adjusted odds of pregnancy were significantly diminished, however, for women with alpha-amylase levels in the middle (10.5-23.6 U/mL; OR, 0.89) or highest tertile (23.7-379.0 U/mL; OR, 0.69), compared with the lowest tertile (0.4-10.4 U/mL; OR, 1.0), she said.

The investigators also used Bayesian statistical techniques to identify the fertile window and estimate day-specific probabilities of conception, taking into account the relevant covariates. Based on this analysis, the probability of pregnancy on day 1 of the fertility window for a 30-year-old, nonsmoking white woman with a partner 2 years older than she and all other covariates centered at the mean, was 26% for women in the lowest alpha-amylase tertile, 24% in the middle tertile, and 20% in the highest tertile, Dr. Lynch said.

The results of a similar analysis in the U.K. cohort showed that conception probabilities increased with increasing quartiles of cortisol for each day during the fertile window, but that the opposite was true for alpha-amylase, as increasing quartiles reduced all day-specific probabilities of conception. The opposing direction of fecundity odds ratios provides evidence that the reduction in fecundity associated with alpha-amylase was mediated via the sympathetic nervous system rather than through the hypothalamic-pituitary-adrenal axis, Dr. Lynch said.

Although the U.S. analysis could not assess the effect of stress over time with only two salivary samples, the data lend further support to the existence and directionality of the stress and fecundity association, she said.

Despite a plethora of evidence that stress negatively impacts pregnancy outcomes, empiric data on stress and conception are surprisingly sparse. A small prospective Australian study involving 13 women found no significant difference in urinary epinephrine, norepinephrine, or cortisol concentrations between conception and nonconception cycles (Hum. Reprod. 1997;12:2324-9).

A newly published study by Dr. Lynch and her colleagues also found no association between self-reported stress, anxiety and depression, and pregnancy after several confounders were controlled for in 339 women, aged 18-40, attempting to conceive (Fertil. Steril. 2012 June 13 [epub ahead of print]).

When asked by the audience how her two studies could come to such different conclusions, Dr. Lynch replied that "when you ask people if they are stressed, if people are chronically stressed they’re not going to perceive this day as any worse than another day in their situation, but that doesn’t mean the body doesn’t respond."

Indeed, the U.K. investigators concluded that alpha-amylase, the principal salivary protein secreted from the parotid gland, may be a "novel biomarker for assessing psychosocial stressors and reproductive end points, as mediated via the sympathetic nervous system." They pointed out that because alpha-amylase is produced locally in the oral cavity, it remains in relatively high concentrations compared with other salivary markers such as cortisol that is released elsewhere in the body by the adrenal gland and transported to the saliva via ultrafiltration.

Dr. Lynch and her colleagues reported no relevant financial disclosures.

MINNEAPOLIS – Increased levels of the stress biomarker alpha-amylase, but not cortisol, are significantly associated with a lower chance of conception, a couple-based, prospective study has shown.

The odds of pregnancy were slashed 31% for women whose salivary levels of alpha-amylase were in the highest tertile, compared with women whose levels were in the lowest tertile after adjustment for such important confounders as the difference between partners’ ages, intercourse during the fertile window and the woman’s age, income, race, parity, smoking, caffeine intake, and alcohol use (odds ratio, 0.69).

Patrice Wendling/IMNG Medical Media

This study is the first in the United States to prospectively examine the association between physiologic stress and fecundity among couples trying to conceive, lead author Courtney D. Lynch, Ph.D., said at the annual meeting of the Society for Pediatric and Perinatal Epidemiologic Research.

"We previously published similar results in a population in the U.K., and we were quite astounded that we found exactly the same thing," she said.

In that study (Fertil. Steril. 2011;95:2184-9), alpha-amylase was negatively associated with fecundity in the first cycle of attempting pregnancy (OR, 0.85) after adjustment for the couples’ age, intercourse frequency during the fertile window, and female alcohol use.

The current analysis was based on 501 couples in Michigan and Texas who were attempting pregnancy and were followed for up to 12 months and then through pregnancy, if pregnancy occurred, as part of the LIFE (Longitudinal Investigation of Fertility and the Environment) study. Cortisol and alpha-amylase concentrations were determined by enzyme immunoassay from salivary samples collected by the women on the day following enrollment and the day following the start of their first menses in the study.

The women, aged 18-40 years, were mostly white (78%), college graduates (75%), and nonsmokers (73%). Their mean age was 30 years, 53% were nulliparous, and 55% were overweight or obese.

Of the 401 couples who completed the protocol, 87% achieved pregnancy and 13% did not.

Complete data evaluable on 393 couples showed no significant differences between women who did or did not become pregnant in mean levels of cortisol (0.46 μg/dL vs. 0.36 μg/dL) or alpha-amylase (23.6 U/mL vs. 32.0 U/mL), said Dr. Lynch, an epidemiologist at Ohio State University in Columbus.

The adjusted odds of pregnancy were similar for women with salivary cortisol in the lowest tertile (0.02-0.30 μg/dL; OR, 1.0), middle tertile (0.31-0.42 μg/dL; OR, 0.90), or highest tertile (0.43-15.60 μg/dL; OR, 0.91).

The adjusted odds of pregnancy were significantly diminished, however, for women with alpha-amylase levels in the middle (10.5-23.6 U/mL; OR, 0.89) or highest tertile (23.7-379.0 U/mL; OR, 0.69), compared with the lowest tertile (0.4-10.4 U/mL; OR, 1.0), she said.

The investigators also used Bayesian statistical techniques to identify the fertile window and estimate day-specific probabilities of conception, taking into account the relevant covariates. Based on this analysis, the probability of pregnancy on day 1 of the fertility window for a 30-year-old, nonsmoking white woman with a partner 2 years older than she and all other covariates centered at the mean, was 26% for women in the lowest alpha-amylase tertile, 24% in the middle tertile, and 20% in the highest tertile, Dr. Lynch said.

The results of a similar analysis in the U.K. cohort showed that conception probabilities increased with increasing quartiles of cortisol for each day during the fertile window, but that the opposite was true for alpha-amylase, as increasing quartiles reduced all day-specific probabilities of conception. The opposing direction of fecundity odds ratios provides evidence that the reduction in fecundity associated with alpha-amylase was mediated via the sympathetic nervous system rather than through the hypothalamic-pituitary-adrenal axis, Dr. Lynch said.

Although the U.S. analysis could not assess the effect of stress over time with only two salivary samples, the data lend further support to the existence and directionality of the stress and fecundity association, she said.

Despite a plethora of evidence that stress negatively impacts pregnancy outcomes, empiric data on stress and conception are surprisingly sparse. A small prospective Australian study involving 13 women found no significant difference in urinary epinephrine, norepinephrine, or cortisol concentrations between conception and nonconception cycles (Hum. Reprod. 1997;12:2324-9).

A newly published study by Dr. Lynch and her colleagues also found no association between self-reported stress, anxiety and depression, and pregnancy after several confounders were controlled for in 339 women, aged 18-40, attempting to conceive (Fertil. Steril. 2012 June 13 [epub ahead of print]).

When asked by the audience how her two studies could come to such different conclusions, Dr. Lynch replied that "when you ask people if they are stressed, if people are chronically stressed they’re not going to perceive this day as any worse than another day in their situation, but that doesn’t mean the body doesn’t respond."

Indeed, the U.K. investigators concluded that alpha-amylase, the principal salivary protein secreted from the parotid gland, may be a "novel biomarker for assessing psychosocial stressors and reproductive end points, as mediated via the sympathetic nervous system." They pointed out that because alpha-amylase is produced locally in the oral cavity, it remains in relatively high concentrations compared with other salivary markers such as cortisol that is released elsewhere in the body by the adrenal gland and transported to the saliva via ultrafiltration.

Dr. Lynch and her colleagues reported no relevant financial disclosures.

MINNEAPOLIS – Increased levels of the stress biomarker alpha-amylase, but not cortisol, are significantly associated with a lower chance of conception, a couple-based, prospective study has shown.

The odds of pregnancy were slashed 31% for women whose salivary levels of alpha-amylase were in the highest tertile, compared with women whose levels were in the lowest tertile after adjustment for such important confounders as the difference between partners’ ages, intercourse during the fertile window and the woman’s age, income, race, parity, smoking, caffeine intake, and alcohol use (odds ratio, 0.69).

Patrice Wendling/IMNG Medical Media

This study is the first in the United States to prospectively examine the association between physiologic stress and fecundity among couples trying to conceive, lead author Courtney D. Lynch, Ph.D., said at the annual meeting of the Society for Pediatric and Perinatal Epidemiologic Research.

"We previously published similar results in a population in the U.K., and we were quite astounded that we found exactly the same thing," she said.

In that study (Fertil. Steril. 2011;95:2184-9), alpha-amylase was negatively associated with fecundity in the first cycle of attempting pregnancy (OR, 0.85) after adjustment for the couples’ age, intercourse frequency during the fertile window, and female alcohol use.

The current analysis was based on 501 couples in Michigan and Texas who were attempting pregnancy and were followed for up to 12 months and then through pregnancy, if pregnancy occurred, as part of the LIFE (Longitudinal Investigation of Fertility and the Environment) study. Cortisol and alpha-amylase concentrations were determined by enzyme immunoassay from salivary samples collected by the women on the day following enrollment and the day following the start of their first menses in the study.

The women, aged 18-40 years, were mostly white (78%), college graduates (75%), and nonsmokers (73%). Their mean age was 30 years, 53% were nulliparous, and 55% were overweight or obese.

Of the 401 couples who completed the protocol, 87% achieved pregnancy and 13% did not.

Complete data evaluable on 393 couples showed no significant differences between women who did or did not become pregnant in mean levels of cortisol (0.46 μg/dL vs. 0.36 μg/dL) or alpha-amylase (23.6 U/mL vs. 32.0 U/mL), said Dr. Lynch, an epidemiologist at Ohio State University in Columbus.

The adjusted odds of pregnancy were similar for women with salivary cortisol in the lowest tertile (0.02-0.30 μg/dL; OR, 1.0), middle tertile (0.31-0.42 μg/dL; OR, 0.90), or highest tertile (0.43-15.60 μg/dL; OR, 0.91).

The adjusted odds of pregnancy were significantly diminished, however, for women with alpha-amylase levels in the middle (10.5-23.6 U/mL; OR, 0.89) or highest tertile (23.7-379.0 U/mL; OR, 0.69), compared with the lowest tertile (0.4-10.4 U/mL; OR, 1.0), she said.

The investigators also used Bayesian statistical techniques to identify the fertile window and estimate day-specific probabilities of conception, taking into account the relevant covariates. Based on this analysis, the probability of pregnancy on day 1 of the fertility window for a 30-year-old, nonsmoking white woman with a partner 2 years older than she and all other covariates centered at the mean, was 26% for women in the lowest alpha-amylase tertile, 24% in the middle tertile, and 20% in the highest tertile, Dr. Lynch said.

The results of a similar analysis in the U.K. cohort showed that conception probabilities increased with increasing quartiles of cortisol for each day during the fertile window, but that the opposite was true for alpha-amylase, as increasing quartiles reduced all day-specific probabilities of conception. The opposing direction of fecundity odds ratios provides evidence that the reduction in fecundity associated with alpha-amylase was mediated via the sympathetic nervous system rather than through the hypothalamic-pituitary-adrenal axis, Dr. Lynch said.

Although the U.S. analysis could not assess the effect of stress over time with only two salivary samples, the data lend further support to the existence and directionality of the stress and fecundity association, she said.

Despite a plethora of evidence that stress negatively impacts pregnancy outcomes, empiric data on stress and conception are surprisingly sparse. A small prospective Australian study involving 13 women found no significant difference in urinary epinephrine, norepinephrine, or cortisol concentrations between conception and nonconception cycles (Hum. Reprod. 1997;12:2324-9).

A newly published study by Dr. Lynch and her colleagues also found no association between self-reported stress, anxiety and depression, and pregnancy after several confounders were controlled for in 339 women, aged 18-40, attempting to conceive (Fertil. Steril. 2012 June 13 [epub ahead of print]).

When asked by the audience how her two studies could come to such different conclusions, Dr. Lynch replied that "when you ask people if they are stressed, if people are chronically stressed they’re not going to perceive this day as any worse than another day in their situation, but that doesn’t mean the body doesn’t respond."

Indeed, the U.K. investigators concluded that alpha-amylase, the principal salivary protein secreted from the parotid gland, may be a "novel biomarker for assessing psychosocial stressors and reproductive end points, as mediated via the sympathetic nervous system." They pointed out that because alpha-amylase is produced locally in the oral cavity, it remains in relatively high concentrations compared with other salivary markers such as cortisol that is released elsewhere in the body by the adrenal gland and transported to the saliva via ultrafiltration.

Dr. Lynch and her colleagues reported no relevant financial disclosures.

MINNEAPOLIS – Extremes in prepregnancy body mass index are linked with slower mental development, an analysis of a large, nationally representative cohort suggests.

 After researchers adjusted for sociodemographics, children whose mothers were obese or underweight were 1.5-times more likely than were children of normal-weight mothers to have delayed mental development at 2 years.

No such association with body mass index (BMI) was observed for motor skills.

Given the obesity epidemic, the findings have implications for pre- and inter-conception care, early intervention programs, and obesity prevention and policy, Stefanie Hinkle, Ph.D., said at the meeting.

"Focusing on obesity in children is a particular concern given they our next generation of mothers," she said at the annual meeting of the Society for Pediatric and Perinatal Epidemiologic Research.

The analysis included 6,850 children from the Early Childhood Longitudinal Study–Birth Cohort, a nationally representative sample of 3.6 million children born in 2001. At about two years of age, certified interviewers used a validated shortened version of the Bayley Scales of Infant Development II to assess mental and psychomotor development.

At 9 months postpartum, 5% of mothers reported a prepregnancy BMI categorized as underweight (less than 18.5 kg/m²); 56% normal weight (18.5-24.9 kg/m²); 25% overweight (25-29.9 kg/m²); 8% class I obese (30-34.9 kg/m²); and 6% class II & III obese (at least 35 kg/m²).

Compared with children of normal-weight mothers, mental development T scores were significantly lower for children of underweight or class II-III obese mothers. The greatest difference, a gap of 2.13 points, was observed among children of mothers with severe obesity or a BMI of 35 kg/m² or more, said Dr. Hinkle, a postdoctoral fellow with the division of reproductive health, Centers for Disease Control and Prevention in Atlanta.

The adjusted odds for the more clinically relevant endpoint of delayed mental development, defined as at least one standard deviation below reference, were 1.48 for children of underweight moms and 1.50 for those of severely obese moms.

T scores for motor development and delayed motor development were not significantly different based on prepregnancy BMI, Dr. Hinkle said.

During a discussion at the meeting, one attendee asked whether the analysis included low birth-weight infants or took into consideration such factors as parenting styles, home environment or neighborhood environment.

"I’m just a little skeptical that obesity, all by itself, has this direct effect because there are a lot of other things that happen during child development in the first few years," said Russell Kirby, Ph.D., professor of community and family health, University of South Florida, Tampa.

Dr. Hinkle said they adjusted the models for maternal age, race/ethnicity, marital status, parity, years of schooling, smoking during pregnancy, and household poverty at the time of the assessment and for the child’s gender. Additional data were collected on factors relating to the home and will be used in a future analysis of the children at 5 years. The investigators also performed an analysis among low birth-weight infants and the findings were similar.

Session moderator Dr. Fiona Stanley, professor of pediatrics at University of Western Australia in Perth, said single-factor analyses are frustrating given that the pathways into obesity are known to be complex and involve several factors that can influence child outcomes such as maternal mental health, self-esteem and poverty.

"There are many pathways into children not doing well on Bayley scores at age 2, and maternal obesity is a marker for a pathway or set of pathways," she said in an interview. "To target just obesity is not the way forward."

Finally, an attendee pointed out that the effect of factors influencing perinatal IQ often disappears as time goes on.

The Oak Ridge (Tenn.) Institute for Science and Education sponsored the analysis. The Department of Education sponsored the Early Childhood Longitudinal Study–Birth Cohort study. Dr. Hinkle and her coauthors report no relevant conflicts of interest.

MINNEAPOLIS – Extremes in prepregnancy body mass index are linked with slower mental development, an analysis of a large, nationally representative cohort suggests.

 After researchers adjusted for sociodemographics, children whose mothers were obese or underweight were 1.5-times more likely than were children of normal-weight mothers to have delayed mental development at 2 years.

No such association with body mass index (BMI) was observed for motor skills.

Given the obesity epidemic, the findings have implications for pre- and inter-conception care, early intervention programs, and obesity prevention and policy, Stefanie Hinkle, Ph.D., said at the meeting.

"Focusing on obesity in children is a particular concern given they our next generation of mothers," she said at the annual meeting of the Society for Pediatric and Perinatal Epidemiologic Research.

The analysis included 6,850 children from the Early Childhood Longitudinal Study–Birth Cohort, a nationally representative sample of 3.6 million children born in 2001. At about two years of age, certified interviewers used a validated shortened version of the Bayley Scales of Infant Development II to assess mental and psychomotor development.

At 9 months postpartum, 5% of mothers reported a prepregnancy BMI categorized as underweight (less than 18.5 kg/m²); 56% normal weight (18.5-24.9 kg/m²); 25% overweight (25-29.9 kg/m²); 8% class I obese (30-34.9 kg/m²); and 6% class II & III obese (at least 35 kg/m²).

Compared with children of normal-weight mothers, mental development T scores were significantly lower for children of underweight or class II-III obese mothers. The greatest difference, a gap of 2.13 points, was observed among children of mothers with severe obesity or a BMI of 35 kg/m² or more, said Dr. Hinkle, a postdoctoral fellow with the division of reproductive health, Centers for Disease Control and Prevention in Atlanta.

The adjusted odds for the more clinically relevant endpoint of delayed mental development, defined as at least one standard deviation below reference, were 1.48 for children of underweight moms and 1.50 for those of severely obese moms.

T scores for motor development and delayed motor development were not significantly different based on prepregnancy BMI, Dr. Hinkle said.

During a discussion at the meeting, one attendee asked whether the analysis included low birth-weight infants or took into consideration such factors as parenting styles, home environment or neighborhood environment.

"I’m just a little skeptical that obesity, all by itself, has this direct effect because there are a lot of other things that happen during child development in the first few years," said Russell Kirby, Ph.D., professor of community and family health, University of South Florida, Tampa.

Dr. Hinkle said they adjusted the models for maternal age, race/ethnicity, marital status, parity, years of schooling, smoking during pregnancy, and household poverty at the time of the assessment and for the child’s gender. Additional data were collected on factors relating to the home and will be used in a future analysis of the children at 5 years. The investigators also performed an analysis among low birth-weight infants and the findings were similar.

Session moderator Dr. Fiona Stanley, professor of pediatrics at University of Western Australia in Perth, said single-factor analyses are frustrating given that the pathways into obesity are known to be complex and involve several factors that can influence child outcomes such as maternal mental health, self-esteem and poverty.

"There are many pathways into children not doing well on Bayley scores at age 2, and maternal obesity is a marker for a pathway or set of pathways," she said in an interview. "To target just obesity is not the way forward."

Finally, an attendee pointed out that the effect of factors influencing perinatal IQ often disappears as time goes on.

The Oak Ridge (Tenn.) Institute for Science and Education sponsored the analysis. The Department of Education sponsored the Early Childhood Longitudinal Study–Birth Cohort study. Dr. Hinkle and her coauthors report no relevant conflicts of interest.

MINNEAPOLIS – Extremes in prepregnancy body mass index are linked with slower mental development, an analysis of a large, nationally representative cohort suggests.

 After researchers adjusted for sociodemographics, children whose mothers were obese or underweight were 1.5-times more likely than were children of normal-weight mothers to have delayed mental development at 2 years.

No such association with body mass index (BMI) was observed for motor skills.

Given the obesity epidemic, the findings have implications for pre- and inter-conception care, early intervention programs, and obesity prevention and policy, Stefanie Hinkle, Ph.D., said at the meeting.

"Focusing on obesity in children is a particular concern given they our next generation of mothers," she said at the annual meeting of the Society for Pediatric and Perinatal Epidemiologic Research.

The analysis included 6,850 children from the Early Childhood Longitudinal Study–Birth Cohort, a nationally representative sample of 3.6 million children born in 2001. At about two years of age, certified interviewers used a validated shortened version of the Bayley Scales of Infant Development II to assess mental and psychomotor development.

At 9 months postpartum, 5% of mothers reported a prepregnancy BMI categorized as underweight (less than 18.5 kg/m²); 56% normal weight (18.5-24.9 kg/m²); 25% overweight (25-29.9 kg/m²); 8% class I obese (30-34.9 kg/m²); and 6% class II & III obese (at least 35 kg/m²).

Compared with children of normal-weight mothers, mental development T scores were significantly lower for children of underweight or class II-III obese mothers. The greatest difference, a gap of 2.13 points, was observed among children of mothers with severe obesity or a BMI of 35 kg/m² or more, said Dr. Hinkle, a postdoctoral fellow with the division of reproductive health, Centers for Disease Control and Prevention in Atlanta.

The adjusted odds for the more clinically relevant endpoint of delayed mental development, defined as at least one standard deviation below reference, were 1.48 for children of underweight moms and 1.50 for those of severely obese moms.

T scores for motor development and delayed motor development were not significantly different based on prepregnancy BMI, Dr. Hinkle said.

During a discussion at the meeting, one attendee asked whether the analysis included low birth-weight infants or took into consideration such factors as parenting styles, home environment or neighborhood environment.

"I’m just a little skeptical that obesity, all by itself, has this direct effect because there are a lot of other things that happen during child development in the first few years," said Russell Kirby, Ph.D., professor of community and family health, University of South Florida, Tampa.

Dr. Hinkle said they adjusted the models for maternal age, race/ethnicity, marital status, parity, years of schooling, smoking during pregnancy, and household poverty at the time of the assessment and for the child’s gender. Additional data were collected on factors relating to the home and will be used in a future analysis of the children at 5 years. The investigators also performed an analysis among low birth-weight infants and the findings were similar.

Session moderator Dr. Fiona Stanley, professor of pediatrics at University of Western Australia in Perth, said single-factor analyses are frustrating given that the pathways into obesity are known to be complex and involve several factors that can influence child outcomes such as maternal mental health, self-esteem and poverty.

"There are many pathways into children not doing well on Bayley scores at age 2, and maternal obesity is a marker for a pathway or set of pathways," she said in an interview. "To target just obesity is not the way forward."

Finally, an attendee pointed out that the effect of factors influencing perinatal IQ often disappears as time goes on.

The Oak Ridge (Tenn.) Institute for Science and Education sponsored the analysis. The Department of Education sponsored the Early Childhood Longitudinal Study–Birth Cohort study. Dr. Hinkle and her coauthors report no relevant conflicts of interest.

MINNEAPOLIS – Maternal hypertension and intrapartum fever increase the risk for ischemic stroke in infants, a large retrospective analysis suggests.

Gestational diabetes, a known risk factor for maternal hypertension and neonatal hypoglycemia, does not increase stroke risk.

"Additional research is needed to determine the mechanism underlying these associations and to develop effective preventive methods for high-risk infants," Dr. Joshua R. Mann reported at the meeting.

Approximately 2-4 children per 10,000 births experience ischemic stroke in the first 28 days of life. Roughly 60% of infants present immediately, typically with neonatal seizures. In the remaining 40%, stroke is recognized later in childhood during evaluation for abnormal neurologic or cognitive development.

There were 43 cases of ischemic stroke before 30 days of life and 118 additional cases diagnosed from day 30 through 364 days in the retrospective analysis of 226,117 children (199,934 full-term births) born from 2000 through 2007 and enrolled in the South Carolina Medicaid program.

Of these, 37 cases and 96 cases, respectively, had confirmed ischemic strokes, defined as more than one ICD-9 code for ischemic stroke or a single diagnosis of ischemic stroke plus a neurocognitive condition that could be indicative of stroke.

Compared with infants without stroke, maternal hypertension was significantly more common for infants with ischemic stroke before 30 days (32.5% vs. 14%; P value = .0004) and before 365 days (28% vs. 14%; P less than .0001), reported Dr. Mann of family and preventive medicine at the University of South Carolina, Columbia.

Fever at delivery was significantly more common in mothers of infants with stroke prior to 365 days (4.9% vs. 1.2%; P less than .0001), but not in those with stroke before 30 days (4.6% vs. 1.2%; P = .09).

Maternal diabetes was not significant at either time point.

In a logistic regression analysis that adjusted for a broad range of demographic and other confounding risk factors, infants born to mothers with hypertension had more than twice the risk of any stroke, defined as one or more diagnoses indicating ischemic stroke, before 30 days (odds ratio 2.31; P = .0071), or a confirmed ischemic stroke (OR 2.75; P = .0021), he said.

Maternal fever at delivery more than tripled the risk of any ischemic stroke (OR 3.36; P = .048) and quadrupled the risk of confirmed ischemic stroke (OR 4.02; P = .025), he reported in a poster presentation.

Maternal diabetes did not significantly increase the odds of any stroke (OR 0.35; P = .08) or confirmed stroke (OR 0.40; P = .13).

Although it was not the primary goal of the study, the investigators also found multiple child characteristics to be associated with increased odds of any stroke prior to 365 days. The significant covariates were birth trauma (OR 5.99), birth asphyxia (OR 11.42), sickle cell disease (OR 3.58), sickle cell trait (OR 2.45), congenital infection (OR 5.39), neonatal infection (OR 6.06), meningitis (OR 6.05), encephalitis (OR 3.99) and child thrombophilia, which had a staggering odds ratio of 157.99.

There was also evidence of synergy between maternal hypertension and the presence of at least one other risk factor for stroke diagnosed before 365 days.

A recent study among 44 children indicated that the timing of the stroke has a bearing on outcomes. Children who had a stroke between 1 and 6 years had better neuropsychological outcomes than did children who had a stroke before age 1 or after age 6 (Child Neuropsychol. 2011 Dec. 6 [doi:10.1080/09297049.2011.639756]).

The full paper is in press with the journal Developmental Medicine and Child Neurology, Dr. Mann noted.

Funding for the study was provided by a Health Resources Services Administration Maternal Child Health grant. Dr. Mann and his coauthors reported having no disclosures.

MINNEAPOLIS – Maternal hypertension and intrapartum fever increase the risk for ischemic stroke in infants, a large retrospective analysis suggests.

Gestational diabetes, a known risk factor for maternal hypertension and neonatal hypoglycemia, does not increase stroke risk.

"Additional research is needed to determine the mechanism underlying these associations and to develop effective preventive methods for high-risk infants," Dr. Joshua R. Mann reported at the meeting.

Approximately 2-4 children per 10,000 births experience ischemic stroke in the first 28 days of life. Roughly 60% of infants present immediately, typically with neonatal seizures. In the remaining 40%, stroke is recognized later in childhood during evaluation for abnormal neurologic or cognitive development.

There were 43 cases of ischemic stroke before 30 days of life and 118 additional cases diagnosed from day 30 through 364 days in the retrospective analysis of 226,117 children (199,934 full-term births) born from 2000 through 2007 and enrolled in the South Carolina Medicaid program.

Of these, 37 cases and 96 cases, respectively, had confirmed ischemic strokes, defined as more than one ICD-9 code for ischemic stroke or a single diagnosis of ischemic stroke plus a neurocognitive condition that could be indicative of stroke.

Compared with infants without stroke, maternal hypertension was significantly more common for infants with ischemic stroke before 30 days (32.5% vs. 14%; P value = .0004) and before 365 days (28% vs. 14%; P less than .0001), reported Dr. Mann of family and preventive medicine at the University of South Carolina, Columbia.

Fever at delivery was significantly more common in mothers of infants with stroke prior to 365 days (4.9% vs. 1.2%; P less than .0001), but not in those with stroke before 30 days (4.6% vs. 1.2%; P = .09).

Maternal diabetes was not significant at either time point.

In a logistic regression analysis that adjusted for a broad range of demographic and other confounding risk factors, infants born to mothers with hypertension had more than twice the risk of any stroke, defined as one or more diagnoses indicating ischemic stroke, before 30 days (odds ratio 2.31; P = .0071), or a confirmed ischemic stroke (OR 2.75; P = .0021), he said.

Maternal fever at delivery more than tripled the risk of any ischemic stroke (OR 3.36; P = .048) and quadrupled the risk of confirmed ischemic stroke (OR 4.02; P = .025), he reported in a poster presentation.

Maternal diabetes did not significantly increase the odds of any stroke (OR 0.35; P = .08) or confirmed stroke (OR 0.40; P = .13).

Although it was not the primary goal of the study, the investigators also found multiple child characteristics to be associated with increased odds of any stroke prior to 365 days. The significant covariates were birth trauma (OR 5.99), birth asphyxia (OR 11.42), sickle cell disease (OR 3.58), sickle cell trait (OR 2.45), congenital infection (OR 5.39), neonatal infection (OR 6.06), meningitis (OR 6.05), encephalitis (OR 3.99) and child thrombophilia, which had a staggering odds ratio of 157.99.

There was also evidence of synergy between maternal hypertension and the presence of at least one other risk factor for stroke diagnosed before 365 days.

A recent study among 44 children indicated that the timing of the stroke has a bearing on outcomes. Children who had a stroke between 1 and 6 years had better neuropsychological outcomes than did children who had a stroke before age 1 or after age 6 (Child Neuropsychol. 2011 Dec. 6 [doi:10.1080/09297049.2011.639756]).

The full paper is in press with the journal Developmental Medicine and Child Neurology, Dr. Mann noted.

Funding for the study was provided by a Health Resources Services Administration Maternal Child Health grant. Dr. Mann and his coauthors reported having no disclosures.

MINNEAPOLIS – Maternal hypertension and intrapartum fever increase the risk for ischemic stroke in infants, a large retrospective analysis suggests.

Gestational diabetes, a known risk factor for maternal hypertension and neonatal hypoglycemia, does not increase stroke risk.

"Additional research is needed to determine the mechanism underlying these associations and to develop effective preventive methods for high-risk infants," Dr. Joshua R. Mann reported at the meeting.

Approximately 2-4 children per 10,000 births experience ischemic stroke in the first 28 days of life. Roughly 60% of infants present immediately, typically with neonatal seizures. In the remaining 40%, stroke is recognized later in childhood during evaluation for abnormal neurologic or cognitive development.

There were 43 cases of ischemic stroke before 30 days of life and 118 additional cases diagnosed from day 30 through 364 days in the retrospective analysis of 226,117 children (199,934 full-term births) born from 2000 through 2007 and enrolled in the South Carolina Medicaid program.

Of these, 37 cases and 96 cases, respectively, had confirmed ischemic strokes, defined as more than one ICD-9 code for ischemic stroke or a single diagnosis of ischemic stroke plus a neurocognitive condition that could be indicative of stroke.

Compared with infants without stroke, maternal hypertension was significantly more common for infants with ischemic stroke before 30 days (32.5% vs. 14%; P value = .0004) and before 365 days (28% vs. 14%; P less than .0001), reported Dr. Mann of family and preventive medicine at the University of South Carolina, Columbia.

Fever at delivery was significantly more common in mothers of infants with stroke prior to 365 days (4.9% vs. 1.2%; P less than .0001), but not in those with stroke before 30 days (4.6% vs. 1.2%; P = .09).

Maternal diabetes was not significant at either time point.

In a logistic regression analysis that adjusted for a broad range of demographic and other confounding risk factors, infants born to mothers with hypertension had more than twice the risk of any stroke, defined as one or more diagnoses indicating ischemic stroke, before 30 days (odds ratio 2.31; P = .0071), or a confirmed ischemic stroke (OR 2.75; P = .0021), he said.

Maternal fever at delivery more than tripled the risk of any ischemic stroke (OR 3.36; P = .048) and quadrupled the risk of confirmed ischemic stroke (OR 4.02; P = .025), he reported in a poster presentation.

Maternal diabetes did not significantly increase the odds of any stroke (OR 0.35; P = .08) or confirmed stroke (OR 0.40; P = .13).

Although it was not the primary goal of the study, the investigators also found multiple child characteristics to be associated with increased odds of any stroke prior to 365 days. The significant covariates were birth trauma (OR 5.99), birth asphyxia (OR 11.42), sickle cell disease (OR 3.58), sickle cell trait (OR 2.45), congenital infection (OR 5.39), neonatal infection (OR 6.06), meningitis (OR 6.05), encephalitis (OR 3.99) and child thrombophilia, which had a staggering odds ratio of 157.99.

There was also evidence of synergy between maternal hypertension and the presence of at least one other risk factor for stroke diagnosed before 365 days.

A recent study among 44 children indicated that the timing of the stroke has a bearing on outcomes. Children who had a stroke between 1 and 6 years had better neuropsychological outcomes than did children who had a stroke before age 1 or after age 6 (Child Neuropsychol. 2011 Dec. 6 [doi:10.1080/09297049.2011.639756]).

The full paper is in press with the journal Developmental Medicine and Child Neurology, Dr. Mann noted.

Funding for the study was provided by a Health Resources Services Administration Maternal Child Health grant. Dr. Mann and his coauthors reported having no disclosures.

CHICAGO – The diagnostic accuracy of FDG-PET in lung cancer performed below previous reports and varied widely among U.S. centers in a secondary analysis of a large phase III clinical trial.

"FDG-PET performed poorly for diagnosing non–small cell lung cancer in a national sample of clinical stage 1 patients," Dr. Eric L. Grogan said at the annual meeting of the American Society of Clinical Oncology.

Patrice Wendling/IMNG Medical Media

The current National Comprehensive Cancer Network guidelines recommend fluorodeoxyglucose positron emission tomography (FDG-PET) for the diagnosis of NSCLC based on studies showing a high degree of accuracy for this diagnostic tool, notably a sensitivity of 94% and a median specificity of 83% in a meta-analysis of 40 studies (JAMA 2001;285:914-24).

Others have reported, however, that FDG-PET performs poorly at single institutions in regions of endemic fungal lung diseases (Ann. Thor. Surg. 2011;92:428-32 and Lung Cancer 2002;36:297-301), observed Dr. Grogan, of Vanderbilt-Ingram Cancer Center in Nashville, Tenn.

Among 682 patients in the American College of Surgeons Oncology Group (ACOSOG) Z4031 trial, the overall accuracy of FDG-PET was 73%, the sensitivity 82%, and the specificity only 31%.

The series is the largest to date evaluating the accuracy of FDG-PET in patients with known or suspected clinical stage 1 NSCLC. In addition, it is generalizable to clinical practice because multiple FDG-PET scanners were used and the scans were performed in community and academic centers and interpreted by multiple radiologists, Dr. Grogan said.

"Results of PET scans in this population should be interpreted cautiously, and reasons for the poor test performance should be explored in other studies," he said.

Discussant Dr. Tetsuya Mitsudomi, chief of thoracic surgery at Aichi Cancer Center Hospital in Nagoya, Japan, said FDG-PET shows reasonable sensitivity, but very low specificity compared with previous studies.

"I think this reflects the real world," he said. "So, the lung cancer diagnosis cannot be made on the basis of PET positivity alone."

Investigators at 51 sites in 39 cities enrolled 969 patients with known or clinically suspicious stage 1 lesions between 2004 and 2006 to evaluate the value of proteomic analysis in diagnosing NSCLC (the results were presented at ASCO 2010). FDG-PET scans were available for 682 patients. All underwent surgical resection. Analyses were performed for all patients and for sites with more than 25 patients.

PET avidity was determined by the radiologist’s description of lesion activity or by the reported maximum standard uptake value (SUV). Avidity was classified in four categories: category 1 was no avidity/not cancer (SUV = 0), category 2 was low avidity/not likely cancer (SUV 0 to less than 2.5), category 3 was avidity/possibly cancer (SUV 2.5 to less than 5.0), and category 4 was high avidity/likely cancer (SUV 5.0 or more).

Among the 682 patients, there were 566 cancers and 116 benign cases. In all, 82% of the cancerous lesions were PET avid, and "surprisingly, 69% of the benign lesions were avid," Dr. Grogan said.

Patients with cancer were significantly older (67 vs. 61 years; P less than .001) and had larger lesions (26 mm vs. 20 mm; P less than .001).

The positive predictive value of FDG-PET was 85% and negative predictive value 26%. This translates into 80 false positives and 101 false negatives. The majority of false positives were granulomas (69%), he observed. Eleven of the false negatives were 10 mm or less.

Not surprising, FDG-PET accuracy improved with lesion size, Dr. Grogan said. The accuracy was less than 50% for lesions less than 20 mm, but greater than 80% for lesions larger than 30 mm. "Above 30 mm, the accuracy did not seem to improve," he observed.

In the eight cities with more than 25 patients, the sensitivity varied significantly, from a low of 67% in Los Angeles to a high of 91% in Durham, N.C. (P = .03), Dr. Grogan said, without explanation. Specificity ranged from 15% in Birmingham, Ala., to 46% in Philadelphia, but this did not reach statistical significance because of the small number of benign cases at each institution (P = .72).

Dr. Mitsudomi said he could not explain the reason for the heterogeneity, especially in terms of the specificity, between centers.

"It’s not possible to remove all the false positives if you use FDG, but newer tracers are being developed and they may increase the specificity rate," he added.

Dr. Grogan reported no disclosures. Dr. Mitsudomi reported having a consulting/advisory role with Boehringer Ingelheim, Kyowa Hakko Kirin, Lilly, and Pfizer, and receiving honoraria from AstraZeneca, Chugai Pharma, Lilly, and Roche.

CHICAGO – The diagnostic accuracy of FDG-PET in lung cancer performed below previous reports and varied widely among U.S. centers in a secondary analysis of a large phase III clinical trial.

"FDG-PET performed poorly for diagnosing non–small cell lung cancer in a national sample of clinical stage 1 patients," Dr. Eric L. Grogan said at the annual meeting of the American Society of Clinical Oncology.

Patrice Wendling/IMNG Medical Media

The current National Comprehensive Cancer Network guidelines recommend fluorodeoxyglucose positron emission tomography (FDG-PET) for the diagnosis of NSCLC based on studies showing a high degree of accuracy for this diagnostic tool, notably a sensitivity of 94% and a median specificity of 83% in a meta-analysis of 40 studies (JAMA 2001;285:914-24).

Others have reported, however, that FDG-PET performs poorly at single institutions in regions of endemic fungal lung diseases (Ann. Thor. Surg. 2011;92:428-32 and Lung Cancer 2002;36:297-301), observed Dr. Grogan, of Vanderbilt-Ingram Cancer Center in Nashville, Tenn.

Among 682 patients in the American College of Surgeons Oncology Group (ACOSOG) Z4031 trial, the overall accuracy of FDG-PET was 73%, the sensitivity 82%, and the specificity only 31%.

The series is the largest to date evaluating the accuracy of FDG-PET in patients with known or suspected clinical stage 1 NSCLC. In addition, it is generalizable to clinical practice because multiple FDG-PET scanners were used and the scans were performed in community and academic centers and interpreted by multiple radiologists, Dr. Grogan said.

"Results of PET scans in this population should be interpreted cautiously, and reasons for the poor test performance should be explored in other studies," he said.

Discussant Dr. Tetsuya Mitsudomi, chief of thoracic surgery at Aichi Cancer Center Hospital in Nagoya, Japan, said FDG-PET shows reasonable sensitivity, but very low specificity compared with previous studies.

"I think this reflects the real world," he said. "So, the lung cancer diagnosis cannot be made on the basis of PET positivity alone."

Investigators at 51 sites in 39 cities enrolled 969 patients with known or clinically suspicious stage 1 lesions between 2004 and 2006 to evaluate the value of proteomic analysis in diagnosing NSCLC (the results were presented at ASCO 2010). FDG-PET scans were available for 682 patients. All underwent surgical resection. Analyses were performed for all patients and for sites with more than 25 patients.

PET avidity was determined by the radiologist’s description of lesion activity or by the reported maximum standard uptake value (SUV). Avidity was classified in four categories: category 1 was no avidity/not cancer (SUV = 0), category 2 was low avidity/not likely cancer (SUV 0 to less than 2.5), category 3 was avidity/possibly cancer (SUV 2.5 to less than 5.0), and category 4 was high avidity/likely cancer (SUV 5.0 or more).

Among the 682 patients, there were 566 cancers and 116 benign cases. In all, 82% of the cancerous lesions were PET avid, and "surprisingly, 69% of the benign lesions were avid," Dr. Grogan said.

Patients with cancer were significantly older (67 vs. 61 years; P less than .001) and had larger lesions (26 mm vs. 20 mm; P less than .001).

The positive predictive value of FDG-PET was 85% and negative predictive value 26%. This translates into 80 false positives and 101 false negatives. The majority of false positives were granulomas (69%), he observed. Eleven of the false negatives were 10 mm or less.

Not surprising, FDG-PET accuracy improved with lesion size, Dr. Grogan said. The accuracy was less than 50% for lesions less than 20 mm, but greater than 80% for lesions larger than 30 mm. "Above 30 mm, the accuracy did not seem to improve," he observed.

In the eight cities with more than 25 patients, the sensitivity varied significantly, from a low of 67% in Los Angeles to a high of 91% in Durham, N.C. (P = .03), Dr. Grogan said, without explanation. Specificity ranged from 15% in Birmingham, Ala., to 46% in Philadelphia, but this did not reach statistical significance because of the small number of benign cases at each institution (P = .72).

Dr. Mitsudomi said he could not explain the reason for the heterogeneity, especially in terms of the specificity, between centers.

"It’s not possible to remove all the false positives if you use FDG, but newer tracers are being developed and they may increase the specificity rate," he added.

Dr. Grogan reported no disclosures. Dr. Mitsudomi reported having a consulting/advisory role with Boehringer Ingelheim, Kyowa Hakko Kirin, Lilly, and Pfizer, and receiving honoraria from AstraZeneca, Chugai Pharma, Lilly, and Roche.

CHICAGO – The diagnostic accuracy of FDG-PET in lung cancer performed below previous reports and varied widely among U.S. centers in a secondary analysis of a large phase III clinical trial.

"FDG-PET performed poorly for diagnosing non–small cell lung cancer in a national sample of clinical stage 1 patients," Dr. Eric L. Grogan said at the annual meeting of the American Society of Clinical Oncology.

Patrice Wendling/IMNG Medical Media

The current National Comprehensive Cancer Network guidelines recommend fluorodeoxyglucose positron emission tomography (FDG-PET) for the diagnosis of NSCLC based on studies showing a high degree of accuracy for this diagnostic tool, notably a sensitivity of 94% and a median specificity of 83% in a meta-analysis of 40 studies (JAMA 2001;285:914-24).

Others have reported, however, that FDG-PET performs poorly at single institutions in regions of endemic fungal lung diseases (Ann. Thor. Surg. 2011;92:428-32 and Lung Cancer 2002;36:297-301), observed Dr. Grogan, of Vanderbilt-Ingram Cancer Center in Nashville, Tenn.

Among 682 patients in the American College of Surgeons Oncology Group (ACOSOG) Z4031 trial, the overall accuracy of FDG-PET was 73%, the sensitivity 82%, and the specificity only 31%.

The series is the largest to date evaluating the accuracy of FDG-PET in patients with known or suspected clinical stage 1 NSCLC. In addition, it is generalizable to clinical practice because multiple FDG-PET scanners were used and the scans were performed in community and academic centers and interpreted by multiple radiologists, Dr. Grogan said.

"Results of PET scans in this population should be interpreted cautiously, and reasons for the poor test performance should be explored in other studies," he said.

Discussant Dr. Tetsuya Mitsudomi, chief of thoracic surgery at Aichi Cancer Center Hospital in Nagoya, Japan, said FDG-PET shows reasonable sensitivity, but very low specificity compared with previous studies.

"I think this reflects the real world," he said. "So, the lung cancer diagnosis cannot be made on the basis of PET positivity alone."

Investigators at 51 sites in 39 cities enrolled 969 patients with known or clinically suspicious stage 1 lesions between 2004 and 2006 to evaluate the value of proteomic analysis in diagnosing NSCLC (the results were presented at ASCO 2010). FDG-PET scans were available for 682 patients. All underwent surgical resection. Analyses were performed for all patients and for sites with more than 25 patients.

PET avidity was determined by the radiologist’s description of lesion activity or by the reported maximum standard uptake value (SUV). Avidity was classified in four categories: category 1 was no avidity/not cancer (SUV = 0), category 2 was low avidity/not likely cancer (SUV 0 to less than 2.5), category 3 was avidity/possibly cancer (SUV 2.5 to less than 5.0), and category 4 was high avidity/likely cancer (SUV 5.0 or more).

Among the 682 patients, there were 566 cancers and 116 benign cases. In all, 82% of the cancerous lesions were PET avid, and "surprisingly, 69% of the benign lesions were avid," Dr. Grogan said.

Patients with cancer were significantly older (67 vs. 61 years; P less than .001) and had larger lesions (26 mm vs. 20 mm; P less than .001).

The positive predictive value of FDG-PET was 85% and negative predictive value 26%. This translates into 80 false positives and 101 false negatives. The majority of false positives were granulomas (69%), he observed. Eleven of the false negatives were 10 mm or less.

Not surprising, FDG-PET accuracy improved with lesion size, Dr. Grogan said. The accuracy was less than 50% for lesions less than 20 mm, but greater than 80% for lesions larger than 30 mm. "Above 30 mm, the accuracy did not seem to improve," he observed.

In the eight cities with more than 25 patients, the sensitivity varied significantly, from a low of 67% in Los Angeles to a high of 91% in Durham, N.C. (P = .03), Dr. Grogan said, without explanation. Specificity ranged from 15% in Birmingham, Ala., to 46% in Philadelphia, but this did not reach statistical significance because of the small number of benign cases at each institution (P = .72).

Dr. Mitsudomi said he could not explain the reason for the heterogeneity, especially in terms of the specificity, between centers.

"It’s not possible to remove all the false positives if you use FDG, but newer tracers are being developed and they may increase the specificity rate," he added.

Dr. Grogan reported no disclosures. Dr. Mitsudomi reported having a consulting/advisory role with Boehringer Ingelheim, Kyowa Hakko Kirin, Lilly, and Pfizer, and receiving honoraria from AstraZeneca, Chugai Pharma, Lilly, and Roche.

MINNEAPOLIS – Improved access to health care appears to be contributing to a rise in attention-deficit/hyperactivity disorder diagnoses among poor children, a national study has found.

Although many factors may be contributing to the rise in ADHD diagnoses among poor children, access to health care through public insurance programs may have played a role, according to Patricia Pastor, Ph.D., who was one of the study coauthors. Since 1997, there has been a significant decline in the number of uninsured poor children because of the expansion of the Children’s Health Insurance Program (CHIP) and Medicaid.

Between 1999 and 2010, the percentage of poor children diagnosed with ADHD increased from 8% to 12%. At the same time, public insurance coverage among these children increased significantly from 40% to 69%, noted Dr. Pastor, of the National Center for Health Statistics, Centers for Disease Control and Prevention. The percentage of poor children covered by public insurance and diagnosed with ADHD also increased from 10% to 14%, but this did not reach statistical significance.

The analysis included 35,896 children, aged 7-11 years, who part of the National Health Interview Survey, an ongoing, nationally representative, in-person household survey. Diagnosed ADHD was identified by the following question: "Has a doctor or health professional ever told you that your child had attention deficit hyperactivity disorder or attention deficit disorder?" Poverty status was based on reported and imputed family income and size. "Poor" children had family incomes less than 200% of the poverty level, while those classified as "non-poor" had family incomes 200% or more of the poverty level.

Between 1999 and 2010, there was an upward trend in the percentage of all children diagnosed with ADHD, increasing by 2% annually, reported Dr. Pastor and her coauthor Cynthia A. Reuben, M.A., also with the CDC. The percentage of non-poor children diagnosed with ADHD remained flat at about 7% during this time period, varying by just 0.2% annually. This compares with an annual percent change (APC) of 2.9% among poor children.

Over the same time period, the percentage of poor children with private health insurance coverage dropped significantly from 35% to 20%, Dr. Pastor said. This was offset by the rise in children on public insurance, lowering the overall number of poor children without insurance from 22% to 12% between 1999 and 2010.

Logistic regression analysis – adjusted for such confounders as age, sex, race, and ethnicity – revealed a significant increase over time in diagnosed ADHD among poor children, but not among non-poor children. When the model was further adjusted to include insurance coverage, the increased risk of an ADHD diagnosis among poor children declined to 1.0, but was not totally eliminated.

"So clearly there were other factors associated with this significant upward trend of diagnosed ADHD in poor children," said Dr. Pastor. Future analyses will explore these factors, such as changes in diagnostic practices of health care providers and in special education programs.

A meeting attendee expressed surprise that the increase in ADHD diagnoses was seen only in the public sector, and asked whether a similar rise was not seen among families with private insurance because they still face costly copayments for tests to diagnosis ADHD.

Dr. Pastor said the diagnosis of ADHD was based on parental report and that a different data set would be needed to tease out the influence of copayments on ADHD trends. "We don’t know what parents had to do to get those diagnoses, and I think that is one of the limitations of our data source," she said.

Session moderator Dr. Fiona Stanley, a professor of pediatrics at the University of Western Australia in Perth, said in an interview that she believes the increase in diagnosed ADHD among the poor does not represent a real increase in the incidence of the disorder, but rather that "more families are coming forward because they can."

She said the study is extremely important because the "usual pattern that we see for ADHD and autism is that poor people aren’t in the sample," and that they are also unlikely to be diagnosed with ADHD or autism, even in countries with national insurance like Australia.

Once the diagnosis is made, clinicians need to provide a lot of parental support and education to poor families on how to manage these children, Dr. Stanley advised.

"Many drugs now, particularly psychotropic drugs, are being given off label with no evidence of what they’re doing in children in primary school up to the teenage years when brains are still developing," she said. "I don’t think we have very good trial evidence of whether they’re effective, and the overdiagnosis of mental illness, particularly in the DSM-V, is horrendous."

Dr. Pastor, Ms. Reuben, and Dr. Stanley reported having no disclosures.

MINNEAPOLIS – Improved access to health care appears to be contributing to a rise in attention-deficit/hyperactivity disorder diagnoses among poor children, a national study has found.

Although many factors may be contributing to the rise in ADHD diagnoses among poor children, access to health care through public insurance programs may have played a role, according to Patricia Pastor, Ph.D., who was one of the study coauthors. Since 1997, there has been a significant decline in the number of uninsured poor children because of the expansion of the Children’s Health Insurance Program (CHIP) and Medicaid.

Between 1999 and 2010, the percentage of poor children diagnosed with ADHD increased from 8% to 12%. At the same time, public insurance coverage among these children increased significantly from 40% to 69%, noted Dr. Pastor, of the National Center for Health Statistics, Centers for Disease Control and Prevention. The percentage of poor children covered by public insurance and diagnosed with ADHD also increased from 10% to 14%, but this did not reach statistical significance.

The analysis included 35,896 children, aged 7-11 years, who part of the National Health Interview Survey, an ongoing, nationally representative, in-person household survey. Diagnosed ADHD was identified by the following question: "Has a doctor or health professional ever told you that your child had attention deficit hyperactivity disorder or attention deficit disorder?" Poverty status was based on reported and imputed family income and size. "Poor" children had family incomes less than 200% of the poverty level, while those classified as "non-poor" had family incomes 200% or more of the poverty level.

Between 1999 and 2010, there was an upward trend in the percentage of all children diagnosed with ADHD, increasing by 2% annually, reported Dr. Pastor and her coauthor Cynthia A. Reuben, M.A., also with the CDC. The percentage of non-poor children diagnosed with ADHD remained flat at about 7% during this time period, varying by just 0.2% annually. This compares with an annual percent change (APC) of 2.9% among poor children.

Over the same time period, the percentage of poor children with private health insurance coverage dropped significantly from 35% to 20%, Dr. Pastor said. This was offset by the rise in children on public insurance, lowering the overall number of poor children without insurance from 22% to 12% between 1999 and 2010.

Logistic regression analysis – adjusted for such confounders as age, sex, race, and ethnicity – revealed a significant increase over time in diagnosed ADHD among poor children, but not among non-poor children. When the model was further adjusted to include insurance coverage, the increased risk of an ADHD diagnosis among poor children declined to 1.0, but was not totally eliminated.

"So clearly there were other factors associated with this significant upward trend of diagnosed ADHD in poor children," said Dr. Pastor. Future analyses will explore these factors, such as changes in diagnostic practices of health care providers and in special education programs.

A meeting attendee expressed surprise that the increase in ADHD diagnoses was seen only in the public sector, and asked whether a similar rise was not seen among families with private insurance because they still face costly copayments for tests to diagnosis ADHD.

Dr. Pastor said the diagnosis of ADHD was based on parental report and that a different data set would be needed to tease out the influence of copayments on ADHD trends. "We don’t know what parents had to do to get those diagnoses, and I think that is one of the limitations of our data source," she said.

Session moderator Dr. Fiona Stanley, a professor of pediatrics at the University of Western Australia in Perth, said in an interview that she believes the increase in diagnosed ADHD among the poor does not represent a real increase in the incidence of the disorder, but rather that "more families are coming forward because they can."

She said the study is extremely important because the "usual pattern that we see for ADHD and autism is that poor people aren’t in the sample," and that they are also unlikely to be diagnosed with ADHD or autism, even in countries with national insurance like Australia.

Once the diagnosis is made, clinicians need to provide a lot of parental support and education to poor families on how to manage these children, Dr. Stanley advised.

"Many drugs now, particularly psychotropic drugs, are being given off label with no evidence of what they’re doing in children in primary school up to the teenage years when brains are still developing," she said. "I don’t think we have very good trial evidence of whether they’re effective, and the overdiagnosis of mental illness, particularly in the DSM-V, is horrendous."

Dr. Pastor, Ms. Reuben, and Dr. Stanley reported having no disclosures.

MINNEAPOLIS – Improved access to health care appears to be contributing to a rise in attention-deficit/hyperactivity disorder diagnoses among poor children, a national study has found.

Although many factors may be contributing to the rise in ADHD diagnoses among poor children, access to health care through public insurance programs may have played a role, according to Patricia Pastor, Ph.D., who was one of the study coauthors. Since 1997, there has been a significant decline in the number of uninsured poor children because of the expansion of the Children’s Health Insurance Program (CHIP) and Medicaid.

Between 1999 and 2010, the percentage of poor children diagnosed with ADHD increased from 8% to 12%. At the same time, public insurance coverage among these children increased significantly from 40% to 69%, noted Dr. Pastor, of the National Center for Health Statistics, Centers for Disease Control and Prevention. The percentage of poor children covered by public insurance and diagnosed with ADHD also increased from 10% to 14%, but this did not reach statistical significance.

The analysis included 35,896 children, aged 7-11 years, who part of the National Health Interview Survey, an ongoing, nationally representative, in-person household survey. Diagnosed ADHD was identified by the following question: "Has a doctor or health professional ever told you that your child had attention deficit hyperactivity disorder or attention deficit disorder?" Poverty status was based on reported and imputed family income and size. "Poor" children had family incomes less than 200% of the poverty level, while those classified as "non-poor" had family incomes 200% or more of the poverty level.

Between 1999 and 2010, there was an upward trend in the percentage of all children diagnosed with ADHD, increasing by 2% annually, reported Dr. Pastor and her coauthor Cynthia A. Reuben, M.A., also with the CDC. The percentage of non-poor children diagnosed with ADHD remained flat at about 7% during this time period, varying by just 0.2% annually. This compares with an annual percent change (APC) of 2.9% among poor children.

Over the same time period, the percentage of poor children with private health insurance coverage dropped significantly from 35% to 20%, Dr. Pastor said. This was offset by the rise in children on public insurance, lowering the overall number of poor children without insurance from 22% to 12% between 1999 and 2010.

Logistic regression analysis – adjusted for such confounders as age, sex, race, and ethnicity – revealed a significant increase over time in diagnosed ADHD among poor children, but not among non-poor children. When the model was further adjusted to include insurance coverage, the increased risk of an ADHD diagnosis among poor children declined to 1.0, but was not totally eliminated.

"So clearly there were other factors associated with this significant upward trend of diagnosed ADHD in poor children," said Dr. Pastor. Future analyses will explore these factors, such as changes in diagnostic practices of health care providers and in special education programs.

A meeting attendee expressed surprise that the increase in ADHD diagnoses was seen only in the public sector, and asked whether a similar rise was not seen among families with private insurance because they still face costly copayments for tests to diagnosis ADHD.

Dr. Pastor said the diagnosis of ADHD was based on parental report and that a different data set would be needed to tease out the influence of copayments on ADHD trends. "We don’t know what parents had to do to get those diagnoses, and I think that is one of the limitations of our data source," she said.

Session moderator Dr. Fiona Stanley, a professor of pediatrics at the University of Western Australia in Perth, said in an interview that she believes the increase in diagnosed ADHD among the poor does not represent a real increase in the incidence of the disorder, but rather that "more families are coming forward because they can."

She said the study is extremely important because the "usual pattern that we see for ADHD and autism is that poor people aren’t in the sample," and that they are also unlikely to be diagnosed with ADHD or autism, even in countries with national insurance like Australia.

Once the diagnosis is made, clinicians need to provide a lot of parental support and education to poor families on how to manage these children, Dr. Stanley advised.

"Many drugs now, particularly psychotropic drugs, are being given off label with no evidence of what they’re doing in children in primary school up to the teenage years when brains are still developing," she said. "I don’t think we have very good trial evidence of whether they’re effective, and the overdiagnosis of mental illness, particularly in the DSM-V, is horrendous."

Dr. Pastor, Ms. Reuben, and Dr. Stanley reported having no disclosures.

CHICAGO – The experimental immunotherapeutic anti-PD-1 agent known as BMS-936558 appears active in non–small cell lung cancer, a malignancy notoriously resistant to immunotherapy.

Among 76 evaluable patients with advanced NSCLC who were enrolled in a multidose phase I trial, 14 patients (18%) had a response. The progression-free survival rate at 24 weeks was 26%.

Patrice Wendling/IMNG Medical Media

The responses were durable, lasting anywhere from 2 to 21 months, Dr. Julie R. Brahmer, an oncologist at Johns Hopkins Hospital in Baltimore, reported at the annual meeting of the American Society of Clinical Oncology.

BMS-936558 is a fully human IgG4 antibody that blocks the programmed death–1 (PD-1) protein. PD-1 is highly expressed by regulatory T cells and tumor-infiltrating lymphocytes in many tumor types, and plays a key role – along with one of its ligands, PD-L1 – in the ability of tumor cells to evade the host’s immune system. Preliminary data suggest a relationship between PD-L1 expression on tumor cells and objective response, Dr. Brahmer noted.

When responses to BMS-936558 were evaluated by histology, the overall response rate was 33% (6 of 18) in patients with squamous histology, and 12.5% (7 of 56) in those with nonsquamous histology.

"Both of these responses are higher than the drugs we have for patients who fail chemotherapy," said discussant Dr. Giuseppe Giaccone of the Medical Oncology Branch at the National Cancer Institute. Moreover, there are no effective targeted agents for NSCLC patients with squamous cell histology.

He pointed out that tumor-infiltrating lymphocytes were associated with better survival in squamous cell carcinomas in a large retrospective analysis of patients with resected lung neoplasms (Ann. Thorac. Surg. 2009;87:365-71), suggesting that there are differences in immunogenicity and that squamous cell histology might be more immunogenic than other types.

Dr. Giaccone went on to highlight a recent phase II study reporting that first-line treatment with another immunomodulatory agent, ipilimumab (Yervoy), added in a phased fashion with paclitaxel (Taxol) and carboplatin chemotherapy, was superior to paclitaxel and carboplatin plus placebo in chemotherapy-naive patients with advanced NSCLC (J. Clin. Oncol. 2012;30:2046-54). Survival was much higher in patients with squamous cell vs. nonsquamous histology, which again suggested a difference between the two types with regard to immunogenicity.

Patients in the current phase I trial with advanced NSCLC and other solid tumors that had progressed after one to five systemic therapies received intravenous BMS-936558 at varying doses until disease progression or clinical deterioration or unacceptable toxicity. Patients who responded or had stable disease, or who had progressive disease but were clinically stable, were treated until they achieved a complete response, worsening progressive disease, or unacceptable toxicity for up to 12 cycles (96 weeks).

In all, 122 patients with NSCLC were evaluable for safety and 76 for clinical activity. At baseline, 60% of the 122 patients had nonsquamous histology, 96% had an ECOG (Eastern Cooperative Oncology Group) performance status of 0-1, and 55% had received at least three prior therapies including platinum-based chemotherapy in 94%, tyrosine-kinase inhibitors in 34%, and radiotherapy in 33%.

The overall response rate was 18% in the 39 patients who were enrolled at the 10-mg/kg dose of BMS-93558, 32% in 19 patients who were given the 3-mg/kg dose, and 6% in 18 patients given the 1-mg/kg dose. The percentage of patients who were free of progression at 24 weeks was 24%, 41%, and 16%, respectively, Dr. Brahmer reported. Three NSCLC patients had a persistent reduction in baseline target lesions in the presence of new lesions, but were not classified as responders for the overall response rate.

Serious adverse events occurred in 14% of the 296 patients in the entire cohort, according to Dr. Suzanne L. Topalian, director of the melanoma program and professor of surgery and oncology at Johns Hopkins University in Baltimore, who presented the results of the main study at the ASCO meeting.

Grade 3/4 adverse events occurred in 10 patients (8%) with NSCLC. There were three drug-related deaths in the study resulting from pneumonitis in two patients with NSCLC and one patient with colorectal cancer, said Dr. Brahmer, who presented the results for patients with NSCLC in a separate session. Investigators saw no apparent relationship between drug dose and adverse event frequency in all treated patients or NSCLC patients.

Dr. Giaccone said the severe pneumonitis was worrisome, but that there is no comparison between the toxicity of BMS-936558 and ipilimumab.

"These represent similar mechanisms, but the side effects are clearly lower with the PD-1 compound," he said, adding that randomized studies will be needed to prove that BMS-936558 is better than the standard of care.

Clinical registration trials of BMS-936558 in patients with NSCLC are planned, Dr. Brahmer said. Recruitment is already underway for a multiarm study of BMS-936558 in combination with three platinum-based doublet chemotherapy regimens in treatment-naïve, stage IIIB/IV NSCLC.

Bristol-Myers Squibb sponsored the study. Dr. Brahmer and Dr. Giaccone report no relevant disclosures.

CHICAGO – The experimental immunotherapeutic anti-PD-1 agent known as BMS-936558 appears active in non–small cell lung cancer, a malignancy notoriously resistant to immunotherapy.

Among 76 evaluable patients with advanced NSCLC who were enrolled in a multidose phase I trial, 14 patients (18%) had a response. The progression-free survival rate at 24 weeks was 26%.

Patrice Wendling/IMNG Medical Media

The responses were durable, lasting anywhere from 2 to 21 months, Dr. Julie R. Brahmer, an oncologist at Johns Hopkins Hospital in Baltimore, reported at the annual meeting of the American Society of Clinical Oncology.

BMS-936558 is a fully human IgG4 antibody that blocks the programmed death–1 (PD-1) protein. PD-1 is highly expressed by regulatory T cells and tumor-infiltrating lymphocytes in many tumor types, and plays a key role – along with one of its ligands, PD-L1 – in the ability of tumor cells to evade the host’s immune system. Preliminary data suggest a relationship between PD-L1 expression on tumor cells and objective response, Dr. Brahmer noted.

When responses to BMS-936558 were evaluated by histology, the overall response rate was 33% (6 of 18) in patients with squamous histology, and 12.5% (7 of 56) in those with nonsquamous histology.

"Both of these responses are higher than the drugs we have for patients who fail chemotherapy," said discussant Dr. Giuseppe Giaccone of the Medical Oncology Branch at the National Cancer Institute. Moreover, there are no effective targeted agents for NSCLC patients with squamous cell histology.

He pointed out that tumor-infiltrating lymphocytes were associated with better survival in squamous cell carcinomas in a large retrospective analysis of patients with resected lung neoplasms (Ann. Thorac. Surg. 2009;87:365-71), suggesting that there are differences in immunogenicity and that squamous cell histology might be more immunogenic than other types.

Dr. Giaccone went on to highlight a recent phase II study reporting that first-line treatment with another immunomodulatory agent, ipilimumab (Yervoy), added in a phased fashion with paclitaxel (Taxol) and carboplatin chemotherapy, was superior to paclitaxel and carboplatin plus placebo in chemotherapy-naive patients with advanced NSCLC (J. Clin. Oncol. 2012;30:2046-54). Survival was much higher in patients with squamous cell vs. nonsquamous histology, which again suggested a difference between the two types with regard to immunogenicity.

Patients in the current phase I trial with advanced NSCLC and other solid tumors that had progressed after one to five systemic therapies received intravenous BMS-936558 at varying doses until disease progression or clinical deterioration or unacceptable toxicity. Patients who responded or had stable disease, or who had progressive disease but were clinically stable, were treated until they achieved a complete response, worsening progressive disease, or unacceptable toxicity for up to 12 cycles (96 weeks).

In all, 122 patients with NSCLC were evaluable for safety and 76 for clinical activity. At baseline, 60% of the 122 patients had nonsquamous histology, 96% had an ECOG (Eastern Cooperative Oncology Group) performance status of 0-1, and 55% had received at least three prior therapies including platinum-based chemotherapy in 94%, tyrosine-kinase inhibitors in 34%, and radiotherapy in 33%.

The overall response rate was 18% in the 39 patients who were enrolled at the 10-mg/kg dose of BMS-93558, 32% in 19 patients who were given the 3-mg/kg dose, and 6% in 18 patients given the 1-mg/kg dose. The percentage of patients who were free of progression at 24 weeks was 24%, 41%, and 16%, respectively, Dr. Brahmer reported. Three NSCLC patients had a persistent reduction in baseline target lesions in the presence of new lesions, but were not classified as responders for the overall response rate.

Serious adverse events occurred in 14% of the 296 patients in the entire cohort, according to Dr. Suzanne L. Topalian, director of the melanoma program and professor of surgery and oncology at Johns Hopkins University in Baltimore, who presented the results of the main study at the ASCO meeting.

Grade 3/4 adverse events occurred in 10 patients (8%) with NSCLC. There were three drug-related deaths in the study resulting from pneumonitis in two patients with NSCLC and one patient with colorectal cancer, said Dr. Brahmer, who presented the results for patients with NSCLC in a separate session. Investigators saw no apparent relationship between drug dose and adverse event frequency in all treated patients or NSCLC patients.

Dr. Giaccone said the severe pneumonitis was worrisome, but that there is no comparison between the toxicity of BMS-936558 and ipilimumab.

"These represent similar mechanisms, but the side effects are clearly lower with the PD-1 compound," he said, adding that randomized studies will be needed to prove that BMS-936558 is better than the standard of care.

Clinical registration trials of BMS-936558 in patients with NSCLC are planned, Dr. Brahmer said. Recruitment is already underway for a multiarm study of BMS-936558 in combination with three platinum-based doublet chemotherapy regimens in treatment-naïve, stage IIIB/IV NSCLC.

Bristol-Myers Squibb sponsored the study. Dr. Brahmer and Dr. Giaccone report no relevant disclosures.

CHICAGO – The experimental immunotherapeutic anti-PD-1 agent known as BMS-936558 appears active in non–small cell lung cancer, a malignancy notoriously resistant to immunotherapy.

Among 76 evaluable patients with advanced NSCLC who were enrolled in a multidose phase I trial, 14 patients (18%) had a response. The progression-free survival rate at 24 weeks was 26%.

Patrice Wendling/IMNG Medical Media

The responses were durable, lasting anywhere from 2 to 21 months, Dr. Julie R. Brahmer, an oncologist at Johns Hopkins Hospital in Baltimore, reported at the annual meeting of the American Society of Clinical Oncology.

BMS-936558 is a fully human IgG4 antibody that blocks the programmed death–1 (PD-1) protein. PD-1 is highly expressed by regulatory T cells and tumor-infiltrating lymphocytes in many tumor types, and plays a key role – along with one of its ligands, PD-L1 – in the ability of tumor cells to evade the host’s immune system. Preliminary data suggest a relationship between PD-L1 expression on tumor cells and objective response, Dr. Brahmer noted.

When responses to BMS-936558 were evaluated by histology, the overall response rate was 33% (6 of 18) in patients with squamous histology, and 12.5% (7 of 56) in those with nonsquamous histology.

"Both of these responses are higher than the drugs we have for patients who fail chemotherapy," said discussant Dr. Giuseppe Giaccone of the Medical Oncology Branch at the National Cancer Institute. Moreover, there are no effective targeted agents for NSCLC patients with squamous cell histology.

He pointed out that tumor-infiltrating lymphocytes were associated with better survival in squamous cell carcinomas in a large retrospective analysis of patients with resected lung neoplasms (Ann. Thorac. Surg. 2009;87:365-71), suggesting that there are differences in immunogenicity and that squamous cell histology might be more immunogenic than other types.

Dr. Giaccone went on to highlight a recent phase II study reporting that first-line treatment with another immunomodulatory agent, ipilimumab (Yervoy), added in a phased fashion with paclitaxel (Taxol) and carboplatin chemotherapy, was superior to paclitaxel and carboplatin plus placebo in chemotherapy-naive patients with advanced NSCLC (J. Clin. Oncol. 2012;30:2046-54). Survival was much higher in patients with squamous cell vs. nonsquamous histology, which again suggested a difference between the two types with regard to immunogenicity.

Patients in the current phase I trial with advanced NSCLC and other solid tumors that had progressed after one to five systemic therapies received intravenous BMS-936558 at varying doses until disease progression or clinical deterioration or unacceptable toxicity. Patients who responded or had stable disease, or who had progressive disease but were clinically stable, were treated until they achieved a complete response, worsening progressive disease, or unacceptable toxicity for up to 12 cycles (96 weeks).

In all, 122 patients with NSCLC were evaluable for safety and 76 for clinical activity. At baseline, 60% of the 122 patients had nonsquamous histology, 96% had an ECOG (Eastern Cooperative Oncology Group) performance status of 0-1, and 55% had received at least three prior therapies including platinum-based chemotherapy in 94%, tyrosine-kinase inhibitors in 34%, and radiotherapy in 33%.

The overall response rate was 18% in the 39 patients who were enrolled at the 10-mg/kg dose of BMS-93558, 32% in 19 patients who were given the 3-mg/kg dose, and 6% in 18 patients given the 1-mg/kg dose. The percentage of patients who were free of progression at 24 weeks was 24%, 41%, and 16%, respectively, Dr. Brahmer reported. Three NSCLC patients had a persistent reduction in baseline target lesions in the presence of new lesions, but were not classified as responders for the overall response rate.

Serious adverse events occurred in 14% of the 296 patients in the entire cohort, according to Dr. Suzanne L. Topalian, director of the melanoma program and professor of surgery and oncology at Johns Hopkins University in Baltimore, who presented the results of the main study at the ASCO meeting.

Grade 3/4 adverse events occurred in 10 patients (8%) with NSCLC. There were three drug-related deaths in the study resulting from pneumonitis in two patients with NSCLC and one patient with colorectal cancer, said Dr. Brahmer, who presented the results for patients with NSCLC in a separate session. Investigators saw no apparent relationship between drug dose and adverse event frequency in all treated patients or NSCLC patients.

Dr. Giaccone said the severe pneumonitis was worrisome, but that there is no comparison between the toxicity of BMS-936558 and ipilimumab.

"These represent similar mechanisms, but the side effects are clearly lower with the PD-1 compound," he said, adding that randomized studies will be needed to prove that BMS-936558 is better than the standard of care.

Clinical registration trials of BMS-936558 in patients with NSCLC are planned, Dr. Brahmer said. Recruitment is already underway for a multiarm study of BMS-936558 in combination with three platinum-based doublet chemotherapy regimens in treatment-naïve, stage IIIB/IV NSCLC.

Bristol-Myers Squibb sponsored the study. Dr. Brahmer and Dr. Giaccone report no relevant disclosures.

CHICAGO – Researchers are beginning to unravel the genomics of squamous cell lung cancer, revealing a disease characterized by complex genomes with frequent and unique rearrangements.

Exome and RNA sequence analyses of 178 patients identified 48,690 nonsilent mutations in total, Dr. Ramaswamy Govindan reported at the annual meeting of the American Society of Clinical Oncology.

Patrice Wendling/IMNG Medical Media

"This is not a disease like CML [chronic myeloid leukemia] with one mutation," he said. "This is a tobacco-related lung cancer with an average of 228 nonsilent mutations per tumor."

Squamous cell lung cancer was found to have 8.3 somatic mutations/megabase, far surpassing, for example, the 0.5 mutations/megabase found in acute myeloid leukemia. The average number of mutations was 360/tumor.

"It’s quite significant the amount of mutational burden," Dr. Govindan remarked. "Granted many of them are passenger mutations, but still it’s a fairly disordered genome."

Dr. Govindan and his fellow researchers with the Cancer Genome Atlas (TCGA) Lung Cancer Project are attempting to characterize the poorly understood genomic and epigenomic landscape of lung squamous cell carcinoma (LSCC), and to identify potential therapeutic targets. No molecularly targeted therapy has been approved for use in LSCC, which accounts for roughly 30% of lung cancer deaths or 45,000 deaths/year in the United States.

The researchers hope to sequence about 1,000 lung cancers in the next year, with data presented on 178 LSCC patients, most of whom smoked (96%), were male (74%), and had early stage I/II disease (76%). Their median age was 68 years.

The tumor protein 53 (TP53) gene was almost universally altered in the cohort, along with frequent loss of cyclin-dependent kinase inhibitor 2A (CDKN2A) function, said Dr. Govindan, an oncologist/hematologist and professor of medicine with Washington University School of Medicine in St. Louis. Other significantly mutated genes were phosphatase and tensin homlog (PTEN), Kelch-like ECH-associated protein 1 (KEAP1), nuclear factor-erythroid 2 related factor 2 (NFE2L2), human leukocyte antigen-A (HLA-A) and phosphoinositide-3-kinase catalytic alpha (PIK3CA).

Therapeutic targets were identified in 127 patients or roughly three-fourths of patients with LSCC. "So it’s really rich in targets," he said.

Most of the samples had distinct genes that are significant in terms of therapy and that are altered in a mutually exclusive fashion. Targets include the fibroblast growth factor receptors (FGFR), phosphoinositide-3 (p13) kinase pathway (47%), epidermal growth factor receptor (EGFR)/erythroblastic leukemia viral oncogene homolog 2 (ErbB-2), and the cyclin-cyclin dependant kinase complexes.

Dr. Govindan recommended that existing drugs should be studied in patients with squamous cell lung cancer, but cautioned that, "This doesn’t necessarily mean a drug that is currently inhibiting a p13 kinase will work in squamous cell lung cancer. That requires well-coordinated clinical trials."

Discussant Dr. Tetsuya Mitsudomi, chief of thoracic surgery at Aichi Cancer Center Hospital in Nagoya, Japan, said the research has identified several existing drug targets that should be tested in clinical trials. He pointed to drugs such as the experimental FGFR inhibitor BGJ398 for patients with FGFR1 amplification, p13K inhibitors for PIK3CA mutations, sunitinib (Sutent) for platelet-derived growth factor receptor–alpha amplification or mutation and dasatinib (Sprycel) to target discoidin domain receptor 2 (DDR2) mutations. A response to dasatinib and erlotinib was recently reported in a patient with squamous cell lung cancer harboring a DDR2 mutation (Cancer Discov. 2011;1:78-89), with a phase II trial planned in patients with advanced tumors harboring this mutation (NCT01514864).

The researchers also conducted whole genome sequencing on 19 tumors, detecting an average of 165 rearrangements/tumor. This is far more than has been seen in the TCGA database for breast or colon cancer, Dr. Govindan said.

The analysis also identified frequent loss of CDKN2A function through multiple mechanisms: homozygous deletion in 30%, methylation in 21%, and mutation in 17%. More important, the mechanisms are complimentary, and there is somatic rearrangement resulting in loss of the CDKN2A locus, Dr. Govindan said. The findings are significant because, although CDKN2A loss may result in the same type of phenotype, tumor response to a specific therapy may differ based on the inactivation mechanism.

"Alterations in CDKN2A are significant and we should really look at this in terms of therapy," he said later in the presentation.

mRNA expression profiling confirmed a recent report that lung squamous cell carcinoma is composed of four biologically distinct mRNA expression subtypes, suggesting the need for different therapies (Clin. Cancer Res. 2010;16:4864-75).

In the current analysis, the classical subtype was present in 36% of samples and enriched with p13K alterations, hypermethylation and the highest rate of tobacco use. In contrast, the basal subtype (25%) was characterized by neurofibromin 1 loss, the secretory (24%) by platelet-derived growth factor (PDGF) receptor-alpha alterations and the primitive subtype (15%) with PTEN and retinoblastoma 1 mutations.

Pathway alterations in LSCC fell into two major categories. Not surprisingly, the squamous differentiation pathway was altered in 44% of patients, but the oxidative stress response was also found to be altered in 34% of patients and 62% of those with the classical mRNA subtype. Three mutually exclusive mutations were lost within this pathway: KEAP1 in 12%, NFE2L2 in 19% and cullin 3 in 7%.

Citing the role of oxidative stress in chemotherapy resistance, Dr. Mitsudomi said, "This is really an important discovery."

Finally, Dr. Govindan said the lung cancer community is witnessing a revolution." We are at the dawn of a new era where we are going to study the cancer genomes in its entirety as we have never done before.

"We used to see the alterations in the cancer genes through a key hole and now we can actually have this panoramic view of this through this comprehensive approach."

The full paper on the TCGA Lung Cancer Project findings is expected to be published shortly and will be deposited in a public database, Dr. Govindan said.

Dr. Govindan reports a consulting or advisory role with Bayer, Boehringer Ingelheim, and Merck Serono. The Cancer Genome Atlas is supported by the National Institutes of Health. Dr. Mitsudomi reports a consulting/advisory role with Boehringer Ingelheim, Kyowa Hakko Kirin, Lilly, and Pfizer and honoraria from AstraZeneca, Chugai Pharma, Lilly, and Roche.

CHICAGO – Researchers are beginning to unravel the genomics of squamous cell lung cancer, revealing a disease characterized by complex genomes with frequent and unique rearrangements.

Exome and RNA sequence analyses of 178 patients identified 48,690 nonsilent mutations in total, Dr. Ramaswamy Govindan reported at the annual meeting of the American Society of Clinical Oncology.

Patrice Wendling/IMNG Medical Media

"This is not a disease like CML [chronic myeloid leukemia] with one mutation," he said. "This is a tobacco-related lung cancer with an average of 228 nonsilent mutations per tumor."

Squamous cell lung cancer was found to have 8.3 somatic mutations/megabase, far surpassing, for example, the 0.5 mutations/megabase found in acute myeloid leukemia. The average number of mutations was 360/tumor.

"It’s quite significant the amount of mutational burden," Dr. Govindan remarked. "Granted many of them are passenger mutations, but still it’s a fairly disordered genome."

Dr. Govindan and his fellow researchers with the Cancer Genome Atlas (TCGA) Lung Cancer Project are attempting to characterize the poorly understood genomic and epigenomic landscape of lung squamous cell carcinoma (LSCC), and to identify potential therapeutic targets. No molecularly targeted therapy has been approved for use in LSCC, which accounts for roughly 30% of lung cancer deaths or 45,000 deaths/year in the United States.

The researchers hope to sequence about 1,000 lung cancers in the next year, with data presented on 178 LSCC patients, most of whom smoked (96%), were male (74%), and had early stage I/II disease (76%). Their median age was 68 years.

The tumor protein 53 (TP53) gene was almost universally altered in the cohort, along with frequent loss of cyclin-dependent kinase inhibitor 2A (CDKN2A) function, said Dr. Govindan, an oncologist/hematologist and professor of medicine with Washington University School of Medicine in St. Louis. Other significantly mutated genes were phosphatase and tensin homlog (PTEN), Kelch-like ECH-associated protein 1 (KEAP1), nuclear factor-erythroid 2 related factor 2 (NFE2L2), human leukocyte antigen-A (HLA-A) and phosphoinositide-3-kinase catalytic alpha (PIK3CA).

Therapeutic targets were identified in 127 patients or roughly three-fourths of patients with LSCC. "So it’s really rich in targets," he said.

Most of the samples had distinct genes that are significant in terms of therapy and that are altered in a mutually exclusive fashion. Targets include the fibroblast growth factor receptors (FGFR), phosphoinositide-3 (p13) kinase pathway (47%), epidermal growth factor receptor (EGFR)/erythroblastic leukemia viral oncogene homolog 2 (ErbB-2), and the cyclin-cyclin dependant kinase complexes.

Dr. Govindan recommended that existing drugs should be studied in patients with squamous cell lung cancer, but cautioned that, "This doesn’t necessarily mean a drug that is currently inhibiting a p13 kinase will work in squamous cell lung cancer. That requires well-coordinated clinical trials."

Discussant Dr. Tetsuya Mitsudomi, chief of thoracic surgery at Aichi Cancer Center Hospital in Nagoya, Japan, said the research has identified several existing drug targets that should be tested in clinical trials. He pointed to drugs such as the experimental FGFR inhibitor BGJ398 for patients with FGFR1 amplification, p13K inhibitors for PIK3CA mutations, sunitinib (Sutent) for platelet-derived growth factor receptor–alpha amplification or mutation and dasatinib (Sprycel) to target discoidin domain receptor 2 (DDR2) mutations. A response to dasatinib and erlotinib was recently reported in a patient with squamous cell lung cancer harboring a DDR2 mutation (Cancer Discov. 2011;1:78-89), with a phase II trial planned in patients with advanced tumors harboring this mutation (NCT01514864).

The researchers also conducted whole genome sequencing on 19 tumors, detecting an average of 165 rearrangements/tumor. This is far more than has been seen in the TCGA database for breast or colon cancer, Dr. Govindan said.

The analysis also identified frequent loss of CDKN2A function through multiple mechanisms: homozygous deletion in 30%, methylation in 21%, and mutation in 17%. More important, the mechanisms are complimentary, and there is somatic rearrangement resulting in loss of the CDKN2A locus, Dr. Govindan said. The findings are significant because, although CDKN2A loss may result in the same type of phenotype, tumor response to a specific therapy may differ based on the inactivation mechanism.

"Alterations in CDKN2A are significant and we should really look at this in terms of therapy," he said later in the presentation.

mRNA expression profiling confirmed a recent report that lung squamous cell carcinoma is composed of four biologically distinct mRNA expression subtypes, suggesting the need for different therapies (Clin. Cancer Res. 2010;16:4864-75).

In the current analysis, the classical subtype was present in 36% of samples and enriched with p13K alterations, hypermethylation and the highest rate of tobacco use. In contrast, the basal subtype (25%) was characterized by neurofibromin 1 loss, the secretory (24%) by platelet-derived growth factor (PDGF) receptor-alpha alterations and the primitive subtype (15%) with PTEN and retinoblastoma 1 mutations.

Pathway alterations in LSCC fell into two major categories. Not surprisingly, the squamous differentiation pathway was altered in 44% of patients, but the oxidative stress response was also found to be altered in 34% of patients and 62% of those with the classical mRNA subtype. Three mutually exclusive mutations were lost within this pathway: KEAP1 in 12%, NFE2L2 in 19% and cullin 3 in 7%.

Citing the role of oxidative stress in chemotherapy resistance, Dr. Mitsudomi said, "This is really an important discovery."

Finally, Dr. Govindan said the lung cancer community is witnessing a revolution." We are at the dawn of a new era where we are going to study the cancer genomes in its entirety as we have never done before.

"We used to see the alterations in the cancer genes through a key hole and now we can actually have this panoramic view of this through this comprehensive approach."

The full paper on the TCGA Lung Cancer Project findings is expected to be published shortly and will be deposited in a public database, Dr. Govindan said.

Dr. Govindan reports a consulting or advisory role with Bayer, Boehringer Ingelheim, and Merck Serono. The Cancer Genome Atlas is supported by the National Institutes of Health. Dr. Mitsudomi reports a consulting/advisory role with Boehringer Ingelheim, Kyowa Hakko Kirin, Lilly, and Pfizer and honoraria from AstraZeneca, Chugai Pharma, Lilly, and Roche.

CHICAGO – Researchers are beginning to unravel the genomics of squamous cell lung cancer, revealing a disease characterized by complex genomes with frequent and unique rearrangements.

Exome and RNA sequence analyses of 178 patients identified 48,690 nonsilent mutations in total, Dr. Ramaswamy Govindan reported at the annual meeting of the American Society of Clinical Oncology.

Patrice Wendling/IMNG Medical Media

"This is not a disease like CML [chronic myeloid leukemia] with one mutation," he said. "This is a tobacco-related lung cancer with an average of 228 nonsilent mutations per tumor."

Squamous cell lung cancer was found to have 8.3 somatic mutations/megabase, far surpassing, for example, the 0.5 mutations/megabase found in acute myeloid leukemia. The average number of mutations was 360/tumor.

"It’s quite significant the amount of mutational burden," Dr. Govindan remarked. "Granted many of them are passenger mutations, but still it’s a fairly disordered genome."

Dr. Govindan and his fellow researchers with the Cancer Genome Atlas (TCGA) Lung Cancer Project are attempting to characterize the poorly understood genomic and epigenomic landscape of lung squamous cell carcinoma (LSCC), and to identify potential therapeutic targets. No molecularly targeted therapy has been approved for use in LSCC, which accounts for roughly 30% of lung cancer deaths or 45,000 deaths/year in the United States.

The researchers hope to sequence about 1,000 lung cancers in the next year, with data presented on 178 LSCC patients, most of whom smoked (96%), were male (74%), and had early stage I/II disease (76%). Their median age was 68 years.

The tumor protein 53 (TP53) gene was almost universally altered in the cohort, along with frequent loss of cyclin-dependent kinase inhibitor 2A (CDKN2A) function, said Dr. Govindan, an oncologist/hematologist and professor of medicine with Washington University School of Medicine in St. Louis. Other significantly mutated genes were phosphatase and tensin homlog (PTEN), Kelch-like ECH-associated protein 1 (KEAP1), nuclear factor-erythroid 2 related factor 2 (NFE2L2), human leukocyte antigen-A (HLA-A) and phosphoinositide-3-kinase catalytic alpha (PIK3CA).

Therapeutic targets were identified in 127 patients or roughly three-fourths of patients with LSCC. "So it’s really rich in targets," he said.

Most of the samples had distinct genes that are significant in terms of therapy and that are altered in a mutually exclusive fashion. Targets include the fibroblast growth factor receptors (FGFR), phosphoinositide-3 (p13) kinase pathway (47%), epidermal growth factor receptor (EGFR)/erythroblastic leukemia viral oncogene homolog 2 (ErbB-2), and the cyclin-cyclin dependant kinase complexes.

Dr. Govindan recommended that existing drugs should be studied in patients with squamous cell lung cancer, but cautioned that, "This doesn’t necessarily mean a drug that is currently inhibiting a p13 kinase will work in squamous cell lung cancer. That requires well-coordinated clinical trials."

Discussant Dr. Tetsuya Mitsudomi, chief of thoracic surgery at Aichi Cancer Center Hospital in Nagoya, Japan, said the research has identified several existing drug targets that should be tested in clinical trials. He pointed to drugs such as the experimental FGFR inhibitor BGJ398 for patients with FGFR1 amplification, p13K inhibitors for PIK3CA mutations, sunitinib (Sutent) for platelet-derived growth factor receptor–alpha amplification or mutation and dasatinib (Sprycel) to target discoidin domain receptor 2 (DDR2) mutations. A response to dasatinib and erlotinib was recently reported in a patient with squamous cell lung cancer harboring a DDR2 mutation (Cancer Discov. 2011;1:78-89), with a phase II trial planned in patients with advanced tumors harboring this mutation (NCT01514864).

The researchers also conducted whole genome sequencing on 19 tumors, detecting an average of 165 rearrangements/tumor. This is far more than has been seen in the TCGA database for breast or colon cancer, Dr. Govindan said.

The analysis also identified frequent loss of CDKN2A function through multiple mechanisms: homozygous deletion in 30%, methylation in 21%, and mutation in 17%. More important, the mechanisms are complimentary, and there is somatic rearrangement resulting in loss of the CDKN2A locus, Dr. Govindan said. The findings are significant because, although CDKN2A loss may result in the same type of phenotype, tumor response to a specific therapy may differ based on the inactivation mechanism.

"Alterations in CDKN2A are significant and we should really look at this in terms of therapy," he said later in the presentation.

mRNA expression profiling confirmed a recent report that lung squamous cell carcinoma is composed of four biologically distinct mRNA expression subtypes, suggesting the need for different therapies (Clin. Cancer Res. 2010;16:4864-75).

In the current analysis, the classical subtype was present in 36% of samples and enriched with p13K alterations, hypermethylation and the highest rate of tobacco use. In contrast, the basal subtype (25%) was characterized by neurofibromin 1 loss, the secretory (24%) by platelet-derived growth factor (PDGF) receptor-alpha alterations and the primitive subtype (15%) with PTEN and retinoblastoma 1 mutations.

Pathway alterations in LSCC fell into two major categories. Not surprisingly, the squamous differentiation pathway was altered in 44% of patients, but the oxidative stress response was also found to be altered in 34% of patients and 62% of those with the classical mRNA subtype. Three mutually exclusive mutations were lost within this pathway: KEAP1 in 12%, NFE2L2 in 19% and cullin 3 in 7%.

Citing the role of oxidative stress in chemotherapy resistance, Dr. Mitsudomi said, "This is really an important discovery."

Finally, Dr. Govindan said the lung cancer community is witnessing a revolution." We are at the dawn of a new era where we are going to study the cancer genomes in its entirety as we have never done before.

"We used to see the alterations in the cancer genes through a key hole and now we can actually have this panoramic view of this through this comprehensive approach."

The full paper on the TCGA Lung Cancer Project findings is expected to be published shortly and will be deposited in a public database, Dr. Govindan said.

Dr. Govindan reports a consulting or advisory role with Bayer, Boehringer Ingelheim, and Merck Serono. The Cancer Genome Atlas is supported by the National Institutes of Health. Dr. Mitsudomi reports a consulting/advisory role with Boehringer Ingelheim, Kyowa Hakko Kirin, Lilly, and Pfizer and honoraria from AstraZeneca, Chugai Pharma, Lilly, and Roche.

CHICAGO – Vitamin D₃ can relieve the aches and pains associated with aromatase inhibitor therapy for breast cancer, according to the results of a randomized, double-blind, placebo-controlled trial.

Six months of vitamin D at 30,000 IU per week proved safe and was associated with "less worsening" of musculoskeletal events and fewer overall adverse quality of life events in women starting adjuvant letrozole (Femara) for hormone receptor–positive breast cancer, Dr. Qamar J. Khan reported at the annual meeting of the American Society of Clinical Oncology.

© Kaspri/Fotolia.com

Aromatase inhibitors are often discontinued prematurely because of new or worsening musculoskeletal pain reported in as many as half of women and fatigue in 15%-30%, said Dr. Khan of the University of Kansas Medical Center in Kansas City.

Vitamin D deficiency is thought to contribute to musculoskeletal symptoms, he said, explaining the rationale for the study. It is prevalent in breast cancer patients who have these aches and pains, and in women receiving adjuvant chemotherapy, even with supplementation. A similar syndrome is seen in people with severe vitamin D deficiency, he noted.

A prior pilot study conducted by the investigators suggested that vitamin D at 50,000 IU/wk for 12 weeks may be effective in reducing these symptoms (Breast Cancer Res. 2010;119:111-8).

The current double-blind VITAL (Vitamin D for Arthralgias From Letrozole) trial evenly randomized 160 postmenopausal women with stage I-III hormone receptor–positive invasive breast cancer and a serum vitamin D level of 40 ng/mL or less. All patients received letrozole 2.5 mg daily and the standard daily recommended daily allowance (RDA) of vitamin D 600 IU and calcium 1,200 mg. One cohort also received 30,000 IU of oral vitamin D₃ weekly for 24 weeks; the other was given a placebo.

The two arms were well matched with regard to age, race, body mass index, vitamin D level at baseline, adjuvant chemotherapy, and radiation therapy.

The per-protocol primary end point was the incidence of a musculoskeletal event, defined as worsening of pain using a simple pain intensity scale, worsening disability from musculoskeletal pain using the Health Assessment Questionnaire II, or discontinuation of letrozole because of pain at 6 months. The primary end point also was measured, substituting the quantitative Brief Pain Inventory for the simple pain intensity scale, Dr. Khan said.

Thirteen patients did not complete the study for reasons unrelated to study agents and/or musculoskeletal events, leaving 147 evaluable for efficacy.

At 6 months, 37% of women receiving 30,000 IU vitamin D weekly experienced a per-protocol musculoskeletal event, compared with 51% on placebo (P = .069), based on the simple scale. When the more robust Brief Pain Inventory was used, 61% of controls and 38% of those on vitamin D reported a musculoskeletal event, a difference that reached statistical significance (P = .008), he said.

A significantly higher proportion of women on placebo also had an adverse quality of life event, defined as a musculoskeletal event plus worsening of fatigue (72% vs. 42%; P less than .001).

The median vitamin D level at baseline was 25.1 ng/mL in the control arm and 22.5 ng/mL in the vitamin D group. It hovered at 32 ng/mL at 12 weeks and 31 ng/mL at 24 weeks in the control group, but rose to 53 ng/mL at 12 weeks and 57 ng/mL at 24 weeks in the vitamin D arm (P = .001 at both 12 and 24 weeks).

Baseline levels had little influence on the final level achieved. The sharp rise followed by relatively little gain in the active treatment arm suggests a plateau in the effect of continued vitamin D supplementation, Dr. Khan observed.

One patient in the control arm developed mild hypercalcemia, and three patients in the control arm discontinued early because of a musculoskeletal adverse event. There were no severe adverse events.

Discussant Karen Mustian, Ph.D., of the University of Rochester (N.Y.) Medical Center, said that the trial used well-validated measures and showed no discernable toxicity with 30,000 IU weekly, which is beyond the current RDA. "Therefore it may be promising for helping with these musculoskeletal symptoms and possibly fatigue," she said.

Dr. Mustian asked whether the time needed to achieve a benefit poses a potential problem in terms of patient adherence and whether data are available on the sustainability of the improvements in musculoskeletal symptoms and fatigue.

Dr. Khan said that aromatase inhibitor–induced adverse events tend to peak at about 6 months and that only one study has looked at using higher doses of vitamin D beyond 6 months. The observation that the effect of vitamin D supplementation plateaus at 3-6 months, however, is consistent with other studies.

"After you load the body with vitamin D and ... you keep on giving the same dose, the body just maintains the levels," he said.

Dr. Khan said that additional studies are needed to address long-term sustainability, and that the investigators have proposed a trial to the Southwest Oncology Group for the same intervention for 1-2 years to study a longer-term effect.

Dr. Khan reports honoraria from Abraxis BioScience and Genentech, and research funding from Abraxis and Novartis Roche/Genentech. His coauthors and Dr. Mustian report no disclosures.

CHICAGO – Vitamin D₃ can relieve the aches and pains associated with aromatase inhibitor therapy for breast cancer, according to the results of a randomized, double-blind, placebo-controlled trial.

Six months of vitamin D at 30,000 IU per week proved safe and was associated with "less worsening" of musculoskeletal events and fewer overall adverse quality of life events in women starting adjuvant letrozole (Femara) for hormone receptor–positive breast cancer, Dr. Qamar J. Khan reported at the annual meeting of the American Society of Clinical Oncology.

© Kaspri/Fotolia.com

Aromatase inhibitors are often discontinued prematurely because of new or worsening musculoskeletal pain reported in as many as half of women and fatigue in 15%-30%, said Dr. Khan of the University of Kansas Medical Center in Kansas City.

Vitamin D deficiency is thought to contribute to musculoskeletal symptoms, he said, explaining the rationale for the study. It is prevalent in breast cancer patients who have these aches and pains, and in women receiving adjuvant chemotherapy, even with supplementation. A similar syndrome is seen in people with severe vitamin D deficiency, he noted.

A prior pilot study conducted by the investigators suggested that vitamin D at 50,000 IU/wk for 12 weeks may be effective in reducing these symptoms (Breast Cancer Res. 2010;119:111-8).

The current double-blind VITAL (Vitamin D for Arthralgias From Letrozole) trial evenly randomized 160 postmenopausal women with stage I-III hormone receptor–positive invasive breast cancer and a serum vitamin D level of 40 ng/mL or less. All patients received letrozole 2.5 mg daily and the standard daily recommended daily allowance (RDA) of vitamin D 600 IU and calcium 1,200 mg. One cohort also received 30,000 IU of oral vitamin D₃ weekly for 24 weeks; the other was given a placebo.

The two arms were well matched with regard to age, race, body mass index, vitamin D level at baseline, adjuvant chemotherapy, and radiation therapy.

The per-protocol primary end point was the incidence of a musculoskeletal event, defined as worsening of pain using a simple pain intensity scale, worsening disability from musculoskeletal pain using the Health Assessment Questionnaire II, or discontinuation of letrozole because of pain at 6 months. The primary end point also was measured, substituting the quantitative Brief Pain Inventory for the simple pain intensity scale, Dr. Khan said.

Thirteen patients did not complete the study for reasons unrelated to study agents and/or musculoskeletal events, leaving 147 evaluable for efficacy.

At 6 months, 37% of women receiving 30,000 IU vitamin D weekly experienced a per-protocol musculoskeletal event, compared with 51% on placebo (P = .069), based on the simple scale. When the more robust Brief Pain Inventory was used, 61% of controls and 38% of those on vitamin D reported a musculoskeletal event, a difference that reached statistical significance (P = .008), he said.

A significantly higher proportion of women on placebo also had an adverse quality of life event, defined as a musculoskeletal event plus worsening of fatigue (72% vs. 42%; P less than .001).

The median vitamin D level at baseline was 25.1 ng/mL in the control arm and 22.5 ng/mL in the vitamin D group. It hovered at 32 ng/mL at 12 weeks and 31 ng/mL at 24 weeks in the control group, but rose to 53 ng/mL at 12 weeks and 57 ng/mL at 24 weeks in the vitamin D arm (P = .001 at both 12 and 24 weeks).

Baseline levels had little influence on the final level achieved. The sharp rise followed by relatively little gain in the active treatment arm suggests a plateau in the effect of continued vitamin D supplementation, Dr. Khan observed.

One patient in the control arm developed mild hypercalcemia, and three patients in the control arm discontinued early because of a musculoskeletal adverse event. There were no severe adverse events.

Discussant Karen Mustian, Ph.D., of the University of Rochester (N.Y.) Medical Center, said that the trial used well-validated measures and showed no discernable toxicity with 30,000 IU weekly, which is beyond the current RDA. "Therefore it may be promising for helping with these musculoskeletal symptoms and possibly fatigue," she said.

Dr. Mustian asked whether the time needed to achieve a benefit poses a potential problem in terms of patient adherence and whether data are available on the sustainability of the improvements in musculoskeletal symptoms and fatigue.

Dr. Khan said that aromatase inhibitor–induced adverse events tend to peak at about 6 months and that only one study has looked at using higher doses of vitamin D beyond 6 months. The observation that the effect of vitamin D supplementation plateaus at 3-6 months, however, is consistent with other studies.

"After you load the body with vitamin D and ... you keep on giving the same dose, the body just maintains the levels," he said.

Dr. Khan said that additional studies are needed to address long-term sustainability, and that the investigators have proposed a trial to the Southwest Oncology Group for the same intervention for 1-2 years to study a longer-term effect.

Dr. Khan reports honoraria from Abraxis BioScience and Genentech, and research funding from Abraxis and Novartis Roche/Genentech. His coauthors and Dr. Mustian report no disclosures.

CHICAGO – Vitamin D₃ can relieve the aches and pains associated with aromatase inhibitor therapy for breast cancer, according to the results of a randomized, double-blind, placebo-controlled trial.

Six months of vitamin D at 30,000 IU per week proved safe and was associated with "less worsening" of musculoskeletal events and fewer overall adverse quality of life events in women starting adjuvant letrozole (Femara) for hormone receptor–positive breast cancer, Dr. Qamar J. Khan reported at the annual meeting of the American Society of Clinical Oncology.

© Kaspri/Fotolia.com

Aromatase inhibitors are often discontinued prematurely because of new or worsening musculoskeletal pain reported in as many as half of women and fatigue in 15%-30%, said Dr. Khan of the University of Kansas Medical Center in Kansas City.

Vitamin D deficiency is thought to contribute to musculoskeletal symptoms, he said, explaining the rationale for the study. It is prevalent in breast cancer patients who have these aches and pains, and in women receiving adjuvant chemotherapy, even with supplementation. A similar syndrome is seen in people with severe vitamin D deficiency, he noted.

A prior pilot study conducted by the investigators suggested that vitamin D at 50,000 IU/wk for 12 weeks may be effective in reducing these symptoms (Breast Cancer Res. 2010;119:111-8).

The current double-blind VITAL (Vitamin D for Arthralgias From Letrozole) trial evenly randomized 160 postmenopausal women with stage I-III hormone receptor–positive invasive breast cancer and a serum vitamin D level of 40 ng/mL or less. All patients received letrozole 2.5 mg daily and the standard daily recommended daily allowance (RDA) of vitamin D 600 IU and calcium 1,200 mg. One cohort also received 30,000 IU of oral vitamin D₃ weekly for 24 weeks; the other was given a placebo.

The two arms were well matched with regard to age, race, body mass index, vitamin D level at baseline, adjuvant chemotherapy, and radiation therapy.

The per-protocol primary end point was the incidence of a musculoskeletal event, defined as worsening of pain using a simple pain intensity scale, worsening disability from musculoskeletal pain using the Health Assessment Questionnaire II, or discontinuation of letrozole because of pain at 6 months. The primary end point also was measured, substituting the quantitative Brief Pain Inventory for the simple pain intensity scale, Dr. Khan said.

Thirteen patients did not complete the study for reasons unrelated to study agents and/or musculoskeletal events, leaving 147 evaluable for efficacy.

At 6 months, 37% of women receiving 30,000 IU vitamin D weekly experienced a per-protocol musculoskeletal event, compared with 51% on placebo (P = .069), based on the simple scale. When the more robust Brief Pain Inventory was used, 61% of controls and 38% of those on vitamin D reported a musculoskeletal event, a difference that reached statistical significance (P = .008), he said.

A significantly higher proportion of women on placebo also had an adverse quality of life event, defined as a musculoskeletal event plus worsening of fatigue (72% vs. 42%; P less than .001).

The median vitamin D level at baseline was 25.1 ng/mL in the control arm and 22.5 ng/mL in the vitamin D group. It hovered at 32 ng/mL at 12 weeks and 31 ng/mL at 24 weeks in the control group, but rose to 53 ng/mL at 12 weeks and 57 ng/mL at 24 weeks in the vitamin D arm (P = .001 at both 12 and 24 weeks).

Baseline levels had little influence on the final level achieved. The sharp rise followed by relatively little gain in the active treatment arm suggests a plateau in the effect of continued vitamin D supplementation, Dr. Khan observed.

One patient in the control arm developed mild hypercalcemia, and three patients in the control arm discontinued early because of a musculoskeletal adverse event. There were no severe adverse events.

Discussant Karen Mustian, Ph.D., of the University of Rochester (N.Y.) Medical Center, said that the trial used well-validated measures and showed no discernable toxicity with 30,000 IU weekly, which is beyond the current RDA. "Therefore it may be promising for helping with these musculoskeletal symptoms and possibly fatigue," she said.

Dr. Mustian asked whether the time needed to achieve a benefit poses a potential problem in terms of patient adherence and whether data are available on the sustainability of the improvements in musculoskeletal symptoms and fatigue.

Dr. Khan said that aromatase inhibitor–induced adverse events tend to peak at about 6 months and that only one study has looked at using higher doses of vitamin D beyond 6 months. The observation that the effect of vitamin D supplementation plateaus at 3-6 months, however, is consistent with other studies.

"After you load the body with vitamin D and ... you keep on giving the same dose, the body just maintains the levels," he said.

Dr. Khan said that additional studies are needed to address long-term sustainability, and that the investigators have proposed a trial to the Southwest Oncology Group for the same intervention for 1-2 years to study a longer-term effect.

Dr. Khan reports honoraria from Abraxis BioScience and Genentech, and research funding from Abraxis and Novartis Roche/Genentech. His coauthors and Dr. Mustian report no disclosures.