The devastation of an acute stroke is something relatively few of us have experienced personally, but professionally we see it very regularly. An estimated 690,000-plus adults in the United States suffer an ischemic stroke annually, and an additional 240,000 experience a transient ischemic attack.

The good news is that the current estimated annual rate of future stroke in this patient population (3%-4%) is historically low, thanks to preventive measures, according to the new "Guidelines for the Prevention of Stroke in Patients with Stroke and Transient Ischemic Attack: A Guideline for Healthcare Professionals," which was published online in Stroke in May (Stroke 2014 May 1 [doi: 10.1161/STR.0000000000000024]). This updated guideline gives evidence-based recommendations on secondary stroke prevention as well as primary prevention in those who have suffered a transient ischemic attack (TIA).

©Dušan Zidar/Fotolia.com

This very extensive guide from the American Heart Association and the American Stroke Association addresses a wide variety of scenarios, ranging from general risk factor modification to specific circumstances, such as myocardial infarction and thrombus, cardiomyopathy, pregnancy, arterial dissection, and aortic arch atherosclerosis.

I welcome the recommendation to consider adding clopidogrel 75 mg/day to aspirin for 90 days in patients with a recent (within 30 days) stroke or TIA attributable to high-grade stenosis (70%-99%) of a major intracranial artery. I used to feel rather helpless to improve the long-term outcome in these patients, but now there seems to be something more we can do, other than just using statins and single antiplatelet therapy.

Other new recommendations stress nutrition. One item suggests performing a nutritional assessment for patients with a history of ischemic stroke or TIA. While many patients may never get around to seeing a nutritionist as an outpatient, no matter how often their primary care physician stresses the importance, when they are in the hospital we have a captive audience. So why not order a nutrition consult, along with the consult for physical, occupational, and speech therapy?

After having experienced an acute neurologic event, many patients and their families are highly motivated to make whatever changes are necessary to prevent a future, potentially catastrophic stroke. Reduction of sodium from 3.3 g/day to 2.5 g/day or less is reasonable, according to the guidelines, though lowering intake to less than 1.5 g/day will lower blood pressure even further. A nutritionist’s input into how to attain these levels without eating a diet that tastes like cardboard can be invaluable. The new guidelines also suggest counseling patients to follow a Mediterranean-type diet – emphasizing whole grains, fruits, vegetables, nuts, olive oil, legumes, fish, poultry, and even low-fat dairy products – instead of the traditional low fat diet.

These new recommendations are only the tip of the iceberg, and this document is highly worthwhile for all practicing clinicians.

Dr. Hester is a hospitalist with Baltimore-Washington Medical Center who has a passion for empowering patients to partner in their health care. She is the creator of the Patient Whiz, a patient-engagement app for iOS. Reach her at [email protected].

The devastation of an acute stroke is something relatively few of us have experienced personally, but professionally we see it very regularly. An estimated 690,000-plus adults in the United States suffer an ischemic stroke annually, and an additional 240,000 experience a transient ischemic attack.

The good news is that the current estimated annual rate of future stroke in this patient population (3%-4%) is historically low, thanks to preventive measures, according to the new "Guidelines for the Prevention of Stroke in Patients with Stroke and Transient Ischemic Attack: A Guideline for Healthcare Professionals," which was published online in Stroke in May (Stroke 2014 May 1 [doi: 10.1161/STR.0000000000000024]). This updated guideline gives evidence-based recommendations on secondary stroke prevention as well as primary prevention in those who have suffered a transient ischemic attack (TIA).

©Dušan Zidar/Fotolia.com

This very extensive guide from the American Heart Association and the American Stroke Association addresses a wide variety of scenarios, ranging from general risk factor modification to specific circumstances, such as myocardial infarction and thrombus, cardiomyopathy, pregnancy, arterial dissection, and aortic arch atherosclerosis.

I welcome the recommendation to consider adding clopidogrel 75 mg/day to aspirin for 90 days in patients with a recent (within 30 days) stroke or TIA attributable to high-grade stenosis (70%-99%) of a major intracranial artery. I used to feel rather helpless to improve the long-term outcome in these patients, but now there seems to be something more we can do, other than just using statins and single antiplatelet therapy.

Other new recommendations stress nutrition. One item suggests performing a nutritional assessment for patients with a history of ischemic stroke or TIA. While many patients may never get around to seeing a nutritionist as an outpatient, no matter how often their primary care physician stresses the importance, when they are in the hospital we have a captive audience. So why not order a nutrition consult, along with the consult for physical, occupational, and speech therapy?

After having experienced an acute neurologic event, many patients and their families are highly motivated to make whatever changes are necessary to prevent a future, potentially catastrophic stroke. Reduction of sodium from 3.3 g/day to 2.5 g/day or less is reasonable, according to the guidelines, though lowering intake to less than 1.5 g/day will lower blood pressure even further. A nutritionist’s input into how to attain these levels without eating a diet that tastes like cardboard can be invaluable. The new guidelines also suggest counseling patients to follow a Mediterranean-type diet – emphasizing whole grains, fruits, vegetables, nuts, olive oil, legumes, fish, poultry, and even low-fat dairy products – instead of the traditional low fat diet.

These new recommendations are only the tip of the iceberg, and this document is highly worthwhile for all practicing clinicians.

Dr. Hester is a hospitalist with Baltimore-Washington Medical Center who has a passion for empowering patients to partner in their health care. She is the creator of the Patient Whiz, a patient-engagement app for iOS. Reach her at [email protected].

The devastation of an acute stroke is something relatively few of us have experienced personally, but professionally we see it very regularly. An estimated 690,000-plus adults in the United States suffer an ischemic stroke annually, and an additional 240,000 experience a transient ischemic attack.

The good news is that the current estimated annual rate of future stroke in this patient population (3%-4%) is historically low, thanks to preventive measures, according to the new "Guidelines for the Prevention of Stroke in Patients with Stroke and Transient Ischemic Attack: A Guideline for Healthcare Professionals," which was published online in Stroke in May (Stroke 2014 May 1 [doi: 10.1161/STR.0000000000000024]). This updated guideline gives evidence-based recommendations on secondary stroke prevention as well as primary prevention in those who have suffered a transient ischemic attack (TIA).

©Dušan Zidar/Fotolia.com

This very extensive guide from the American Heart Association and the American Stroke Association addresses a wide variety of scenarios, ranging from general risk factor modification to specific circumstances, such as myocardial infarction and thrombus, cardiomyopathy, pregnancy, arterial dissection, and aortic arch atherosclerosis.

I welcome the recommendation to consider adding clopidogrel 75 mg/day to aspirin for 90 days in patients with a recent (within 30 days) stroke or TIA attributable to high-grade stenosis (70%-99%) of a major intracranial artery. I used to feel rather helpless to improve the long-term outcome in these patients, but now there seems to be something more we can do, other than just using statins and single antiplatelet therapy.

Other new recommendations stress nutrition. One item suggests performing a nutritional assessment for patients with a history of ischemic stroke or TIA. While many patients may never get around to seeing a nutritionist as an outpatient, no matter how often their primary care physician stresses the importance, when they are in the hospital we have a captive audience. So why not order a nutrition consult, along with the consult for physical, occupational, and speech therapy?

After having experienced an acute neurologic event, many patients and their families are highly motivated to make whatever changes are necessary to prevent a future, potentially catastrophic stroke. Reduction of sodium from 3.3 g/day to 2.5 g/day or less is reasonable, according to the guidelines, though lowering intake to less than 1.5 g/day will lower blood pressure even further. A nutritionist’s input into how to attain these levels without eating a diet that tastes like cardboard can be invaluable. The new guidelines also suggest counseling patients to follow a Mediterranean-type diet – emphasizing whole grains, fruits, vegetables, nuts, olive oil, legumes, fish, poultry, and even low-fat dairy products – instead of the traditional low fat diet.

These new recommendations are only the tip of the iceberg, and this document is highly worthwhile for all practicing clinicians.

Dr. Hester is a hospitalist with Baltimore-Washington Medical Center who has a passion for empowering patients to partner in their health care. She is the creator of the Patient Whiz, a patient-engagement app for iOS. Reach her at [email protected].

The National Institute on Drug Abuse has released an updated set of resources to help parents "sort out marijuana myths from science based facts," according to a statement released May 20 by the National Institutes of Health.

Two updated booklets are being released in conjunction with the Substance Abuse and Mental Health Services Administration’s National Prevention Week 2014, which takes place May 18-24.

© Stockphoto4u/iStockphoto.com

"Marijuana Facts for Teens" covers the topics of marijuana’s health consequences in teens, its effect on the developing brain, addiction risk, and updated information about its potential medical benefits. "Marijuana: Facts Parents Need to Know" contains updated guidelines for parents on how to tell if their child is using marijuana and how to discuss the topic with their children.

Both publications have been updated to include new sections on the dangers of synthetic marijuana, the effect of marijuana use on teens’ IQ, and potential therapeutic uses of the drug.

According to the 2013 Monitoring the Future survey, 45.5% of teens will have tried marijuana at least once by the time they graduate high school, and more than 6% of high school seniors report smoking daily.

For more information, visit http://teens.drugabuse.gov/.

[email protected]

The National Institute on Drug Abuse has released an updated set of resources to help parents "sort out marijuana myths from science based facts," according to a statement released May 20 by the National Institutes of Health.

Two updated booklets are being released in conjunction with the Substance Abuse and Mental Health Services Administration’s National Prevention Week 2014, which takes place May 18-24.

© Stockphoto4u/iStockphoto.com

"Marijuana Facts for Teens" covers the topics of marijuana’s health consequences in teens, its effect on the developing brain, addiction risk, and updated information about its potential medical benefits. "Marijuana: Facts Parents Need to Know" contains updated guidelines for parents on how to tell if their child is using marijuana and how to discuss the topic with their children.

Both publications have been updated to include new sections on the dangers of synthetic marijuana, the effect of marijuana use on teens’ IQ, and potential therapeutic uses of the drug.

According to the 2013 Monitoring the Future survey, 45.5% of teens will have tried marijuana at least once by the time they graduate high school, and more than 6% of high school seniors report smoking daily.

For more information, visit http://teens.drugabuse.gov/.

[email protected]

The National Institute on Drug Abuse has released an updated set of resources to help parents "sort out marijuana myths from science based facts," according to a statement released May 20 by the National Institutes of Health.

Two updated booklets are being released in conjunction with the Substance Abuse and Mental Health Services Administration’s National Prevention Week 2014, which takes place May 18-24.

© Stockphoto4u/iStockphoto.com

"Marijuana Facts for Teens" covers the topics of marijuana’s health consequences in teens, its effect on the developing brain, addiction risk, and updated information about its potential medical benefits. "Marijuana: Facts Parents Need to Know" contains updated guidelines for parents on how to tell if their child is using marijuana and how to discuss the topic with their children.

Both publications have been updated to include new sections on the dangers of synthetic marijuana, the effect of marijuana use on teens’ IQ, and potential therapeutic uses of the drug.

According to the 2013 Monitoring the Future survey, 45.5% of teens will have tried marijuana at least once by the time they graduate high school, and more than 6% of high school seniors report smoking daily.

For more information, visit http://teens.drugabuse.gov/.

[email protected]

Data from the Centers for Disease Control and Prevention’s National Ambulatory Medical Center Survey reveal benzodiazepine prescriptions grew by 12.5% per year between 2002 and 2009. Data from the National Health and Nutrition Examination Survey suggest that prescriptions for sleep aids (sedatives and hypnotics) tripled between 1998 and 2006. Four percent of U.S. adults age 20 years or older and 7% of adults age 80 years or older report using a prescription sleep aid in the past month.

Aside from the addictive potential and their limited long-term effectiveness, they may be associated with an increased risk of death.

Dr. Scott Weich and his colleagues at University of Warwick, Coventry, England, analyzed data from a retrospective matched cohort study involving 34,727 patients aged at least 16 years who received prescriptions for anxiolytics or hypnotics and 69,418 patients who did not (BMJ 2014;348:g1996). To reduce the likelihood that patients received a prescription that they did not fill, only patients receiving at least two prescriptions were included. The average follow-up period was 7.6 years. The most commonly prescribed drugs were diazepam (48%), temazepam (35%), zopiclone (34%), and zolpidem (8%).

Significantly higher ratios for mortality were observed with the use of these drugs. Adjusting for potential confounders, the hazard ratio for mortality during the whole follow-up period was significantly elevated for the group receiving any sedative or hypnotic in the first year of recruitment (hazard ratio, 3.32; 95% confidence interval: 3.19-3.45).

Dose responses were observed for study drugs. For example, the HR for patients receiving more than 90 doses during the first year was 4.51 (95% CI: 4.22-4.82). Patients who did not receive study drugs beyond 1 year were less likely to die than those who continued to take them. The authors point out that these data translate into four excess deaths linked to use of these drugs per 100 people over 7.6 years after the initial prescription.

The biggest challenge will be to figure out how best to incorporate this information into our counseling of patients without sounding like we are "fear-mongering." Fear-mongering doesn’t work – it just makes our patients more anxious, when what we really need to do is calm them down.

Cognitive-behavioral therapy works for insomnia, but patients report not having the time. I always start the discussion by telling patients to read the book "No More Sleepless Nights" and to start a sleep log. Amazing what we can learn from this. This as least gets the ball rolling.

Dr. Ebbert is professor of medicine, a general internist at the Mayo Clinic in Rochester, Minn., and a diplomate of the American Board of Addiction Medicine. The opinions expressed are those of the author. Dr. Ebbert does not receive royalties from the sale of "No More Sleepless Nights."

Data from the Centers for Disease Control and Prevention’s National Ambulatory Medical Center Survey reveal benzodiazepine prescriptions grew by 12.5% per year between 2002 and 2009. Data from the National Health and Nutrition Examination Survey suggest that prescriptions for sleep aids (sedatives and hypnotics) tripled between 1998 and 2006. Four percent of U.S. adults age 20 years or older and 7% of adults age 80 years or older report using a prescription sleep aid in the past month.

Aside from the addictive potential and their limited long-term effectiveness, they may be associated with an increased risk of death.

Dr. Scott Weich and his colleagues at University of Warwick, Coventry, England, analyzed data from a retrospective matched cohort study involving 34,727 patients aged at least 16 years who received prescriptions for anxiolytics or hypnotics and 69,418 patients who did not (BMJ 2014;348:g1996). To reduce the likelihood that patients received a prescription that they did not fill, only patients receiving at least two prescriptions were included. The average follow-up period was 7.6 years. The most commonly prescribed drugs were diazepam (48%), temazepam (35%), zopiclone (34%), and zolpidem (8%).

Significantly higher ratios for mortality were observed with the use of these drugs. Adjusting for potential confounders, the hazard ratio for mortality during the whole follow-up period was significantly elevated for the group receiving any sedative or hypnotic in the first year of recruitment (hazard ratio, 3.32; 95% confidence interval: 3.19-3.45).

Dose responses were observed for study drugs. For example, the HR for patients receiving more than 90 doses during the first year was 4.51 (95% CI: 4.22-4.82). Patients who did not receive study drugs beyond 1 year were less likely to die than those who continued to take them. The authors point out that these data translate into four excess deaths linked to use of these drugs per 100 people over 7.6 years after the initial prescription.

The biggest challenge will be to figure out how best to incorporate this information into our counseling of patients without sounding like we are "fear-mongering." Fear-mongering doesn’t work – it just makes our patients more anxious, when what we really need to do is calm them down.

Cognitive-behavioral therapy works for insomnia, but patients report not having the time. I always start the discussion by telling patients to read the book "No More Sleepless Nights" and to start a sleep log. Amazing what we can learn from this. This as least gets the ball rolling.

Dr. Ebbert is professor of medicine, a general internist at the Mayo Clinic in Rochester, Minn., and a diplomate of the American Board of Addiction Medicine. The opinions expressed are those of the author. Dr. Ebbert does not receive royalties from the sale of "No More Sleepless Nights."

Data from the Centers for Disease Control and Prevention’s National Ambulatory Medical Center Survey reveal benzodiazepine prescriptions grew by 12.5% per year between 2002 and 2009. Data from the National Health and Nutrition Examination Survey suggest that prescriptions for sleep aids (sedatives and hypnotics) tripled between 1998 and 2006. Four percent of U.S. adults age 20 years or older and 7% of adults age 80 years or older report using a prescription sleep aid in the past month.

Aside from the addictive potential and their limited long-term effectiveness, they may be associated with an increased risk of death.

Dr. Scott Weich and his colleagues at University of Warwick, Coventry, England, analyzed data from a retrospective matched cohort study involving 34,727 patients aged at least 16 years who received prescriptions for anxiolytics or hypnotics and 69,418 patients who did not (BMJ 2014;348:g1996). To reduce the likelihood that patients received a prescription that they did not fill, only patients receiving at least two prescriptions were included. The average follow-up period was 7.6 years. The most commonly prescribed drugs were diazepam (48%), temazepam (35%), zopiclone (34%), and zolpidem (8%).

Significantly higher ratios for mortality were observed with the use of these drugs. Adjusting for potential confounders, the hazard ratio for mortality during the whole follow-up period was significantly elevated for the group receiving any sedative or hypnotic in the first year of recruitment (hazard ratio, 3.32; 95% confidence interval: 3.19-3.45).

Dose responses were observed for study drugs. For example, the HR for patients receiving more than 90 doses during the first year was 4.51 (95% CI: 4.22-4.82). Patients who did not receive study drugs beyond 1 year were less likely to die than those who continued to take them. The authors point out that these data translate into four excess deaths linked to use of these drugs per 100 people over 7.6 years after the initial prescription.

The biggest challenge will be to figure out how best to incorporate this information into our counseling of patients without sounding like we are "fear-mongering." Fear-mongering doesn’t work – it just makes our patients more anxious, when what we really need to do is calm them down.

Cognitive-behavioral therapy works for insomnia, but patients report not having the time. I always start the discussion by telling patients to read the book "No More Sleepless Nights" and to start a sleep log. Amazing what we can learn from this. This as least gets the ball rolling.

Dr. Ebbert is professor of medicine, a general internist at the Mayo Clinic in Rochester, Minn., and a diplomate of the American Board of Addiction Medicine. The opinions expressed are those of the author. Dr. Ebbert does not receive royalties from the sale of "No More Sleepless Nights."

Researcher in the lab

Credit: NIH

Chemists say they have determined the correct structure of a compound that has shown activity against lymphoma and a range of other cancers.

Their research, published in Angewandte Chemie, focused on a compound called TIC10.

The team showed that TIC10’s structure differs subtly from a version described by another group last year, and the previous structure associated with TIC10 actually describes a molecule that lacks TIC10’s anticancer activity.

The newly identified structure describes a molecule with potent anticancer effects in animals, representing a new family of biologically active structures that can now be explored for possible therapeutic uses.

“This new structure should generate much interest in the cancer research community,” said study author Kim D. Janda, PhD, of The Scripps Research Institute in La Jolla, California.

Antitumor potential

TIC10 was first described in Science Translational Medicine in early 2013. The authors identified the compound, within a library of thousands of molecules maintained by the National Cancer Institute (NCI), for its ability to boost cells’ production of the natural antitumor protein TRAIL. (TIC10 stands for TRAIL-inducing compound #10.)

As a small molecule, TIC10 would be easier to deliver in a therapy than the TRAIL protein itself. The paper’s authors reported that TIC10 was orally active and dramatically shrank a variety of tumors in mice.

Tumors can develop resistance to TRAIL, but Dr Janda had been studying compounds that defeat this resistance. The news about TIC10 therefore got his attention.

“I thought, ‘They have this molecule for upregulating TRAIL, and we have these molecules that can overcome tumor-cell TRAIL resistance—the combination could be important,’” he said.

The original publication on TIC10 included a figure showing its predicted structure. So Dr Janda asked one of his postdoctoral researchers, Jonathan Lockner, to make TIC10 using that information.

Although the original TIC10 research team had seemingly confirmed the predicted structure with mass spectrometry, no one had published a thorough characterization of the TIC10 molecule.

“There were no nuclear magnetic resonance data or X-ray crystallography data, and there was definitely no procedure for the synthesis,” Dr Lockner said. “My background was chemistry, though, so I was able to find a way to synthesize it starting from simple compounds.”

Surprising inactivity

There was just one problem with Dr Lockner’s newly synthesized “TIC10.” When tested, it failed to induce TRAIL expression in cells, even at high doses.

“Of course, I was nervous,” Dr Lockner said. “As a chemist, you never want to make a mistake and give biologists the wrong material.”

To try and verify they had the right material, Dr Janda’s team obtained a sample of TIC10 directly from the NCI.

“When we got that sample and tested it, we saw that it had the expected TRAIL-upregulating effect,” said Nicholas Jacob, a graduate student in the Janda Lab and coauthor of the new paper.

“That prompted us to look more closely at the structures of these 2 compounds.”

The researchers spent months characterizing their own synthesized material and the NCI material, using an array of sophisticated structural analysis tools. They also tested the 2 compounds’ biological effects.

The team eventually concluded that the TIC10 compound from the NCI library does boost TRAIL production in cells and remains promising as the basis for anticancer therapies, but it does not have the structure that was originally published.

The right structure

The originally published structure has a core made of 3 carbon-nitrogen rings in a straight line and does not induce TRAIL activity. The correct, TRAIL-inducing structure differs subtly, with an end ring that sticks out at an angle.

In chemists’ parlance, the 2 compounds are constitutional isomers: a linear imidazolinopyrimidinone and an angular imidazolinopyrimidinone.

And Dr Lockner found that the angular, TRAIL-inducing structure was easier to synthesize than the one originally described.

Now, with the correct molecule in hand and a solid understanding of its structure and synthesis, Dr Janda and his team are moving forward with their original plan to study TIC10 in combination with TRAIL-resistance-thwarting molecules as an anticancer therapy.

The therapeutic implications of TIC10 may even go beyond cancer, according to the researchers. The angular core of the TRAIL-inducing molecule Dr Janda’s team discovered is a novel type of a biologically active structure, or pharmacophore, from which chemists may now be able to build a new class of candidate drugs, possibly for a variety of ailments.

Researcher in the lab

Credit: NIH

Chemists say they have determined the correct structure of a compound that has shown activity against lymphoma and a range of other cancers.

Their research, published in Angewandte Chemie, focused on a compound called TIC10.

The team showed that TIC10’s structure differs subtly from a version described by another group last year, and the previous structure associated with TIC10 actually describes a molecule that lacks TIC10’s anticancer activity.

The newly identified structure describes a molecule with potent anticancer effects in animals, representing a new family of biologically active structures that can now be explored for possible therapeutic uses.

“This new structure should generate much interest in the cancer research community,” said study author Kim D. Janda, PhD, of The Scripps Research Institute in La Jolla, California.

Antitumor potential

TIC10 was first described in Science Translational Medicine in early 2013. The authors identified the compound, within a library of thousands of molecules maintained by the National Cancer Institute (NCI), for its ability to boost cells’ production of the natural antitumor protein TRAIL. (TIC10 stands for TRAIL-inducing compound #10.)

As a small molecule, TIC10 would be easier to deliver in a therapy than the TRAIL protein itself. The paper’s authors reported that TIC10 was orally active and dramatically shrank a variety of tumors in mice.

Tumors can develop resistance to TRAIL, but Dr Janda had been studying compounds that defeat this resistance. The news about TIC10 therefore got his attention.

“I thought, ‘They have this molecule for upregulating TRAIL, and we have these molecules that can overcome tumor-cell TRAIL resistance—the combination could be important,’” he said.

The original publication on TIC10 included a figure showing its predicted structure. So Dr Janda asked one of his postdoctoral researchers, Jonathan Lockner, to make TIC10 using that information.

Although the original TIC10 research team had seemingly confirmed the predicted structure with mass spectrometry, no one had published a thorough characterization of the TIC10 molecule.

“There were no nuclear magnetic resonance data or X-ray crystallography data, and there was definitely no procedure for the synthesis,” Dr Lockner said. “My background was chemistry, though, so I was able to find a way to synthesize it starting from simple compounds.”

Surprising inactivity

There was just one problem with Dr Lockner’s newly synthesized “TIC10.” When tested, it failed to induce TRAIL expression in cells, even at high doses.

“Of course, I was nervous,” Dr Lockner said. “As a chemist, you never want to make a mistake and give biologists the wrong material.”

To try and verify they had the right material, Dr Janda’s team obtained a sample of TIC10 directly from the NCI.

“When we got that sample and tested it, we saw that it had the expected TRAIL-upregulating effect,” said Nicholas Jacob, a graduate student in the Janda Lab and coauthor of the new paper.

“That prompted us to look more closely at the structures of these 2 compounds.”

The researchers spent months characterizing their own synthesized material and the NCI material, using an array of sophisticated structural analysis tools. They also tested the 2 compounds’ biological effects.

The team eventually concluded that the TIC10 compound from the NCI library does boost TRAIL production in cells and remains promising as the basis for anticancer therapies, but it does not have the structure that was originally published.

The right structure

The originally published structure has a core made of 3 carbon-nitrogen rings in a straight line and does not induce TRAIL activity. The correct, TRAIL-inducing structure differs subtly, with an end ring that sticks out at an angle.

In chemists’ parlance, the 2 compounds are constitutional isomers: a linear imidazolinopyrimidinone and an angular imidazolinopyrimidinone.

And Dr Lockner found that the angular, TRAIL-inducing structure was easier to synthesize than the one originally described.

Now, with the correct molecule in hand and a solid understanding of its structure and synthesis, Dr Janda and his team are moving forward with their original plan to study TIC10 in combination with TRAIL-resistance-thwarting molecules as an anticancer therapy.

The therapeutic implications of TIC10 may even go beyond cancer, according to the researchers. The angular core of the TRAIL-inducing molecule Dr Janda’s team discovered is a novel type of a biologically active structure, or pharmacophore, from which chemists may now be able to build a new class of candidate drugs, possibly for a variety of ailments.

Researcher in the lab

Credit: NIH

Chemists say they have determined the correct structure of a compound that has shown activity against lymphoma and a range of other cancers.

Their research, published in Angewandte Chemie, focused on a compound called TIC10.

The team showed that TIC10’s structure differs subtly from a version described by another group last year, and the previous structure associated with TIC10 actually describes a molecule that lacks TIC10’s anticancer activity.

The newly identified structure describes a molecule with potent anticancer effects in animals, representing a new family of biologically active structures that can now be explored for possible therapeutic uses.

“This new structure should generate much interest in the cancer research community,” said study author Kim D. Janda, PhD, of The Scripps Research Institute in La Jolla, California.

Antitumor potential

TIC10 was first described in Science Translational Medicine in early 2013. The authors identified the compound, within a library of thousands of molecules maintained by the National Cancer Institute (NCI), for its ability to boost cells’ production of the natural antitumor protein TRAIL. (TIC10 stands for TRAIL-inducing compound #10.)

As a small molecule, TIC10 would be easier to deliver in a therapy than the TRAIL protein itself. The paper’s authors reported that TIC10 was orally active and dramatically shrank a variety of tumors in mice.

Tumors can develop resistance to TRAIL, but Dr Janda had been studying compounds that defeat this resistance. The news about TIC10 therefore got his attention.

“I thought, ‘They have this molecule for upregulating TRAIL, and we have these molecules that can overcome tumor-cell TRAIL resistance—the combination could be important,’” he said.

The original publication on TIC10 included a figure showing its predicted structure. So Dr Janda asked one of his postdoctoral researchers, Jonathan Lockner, to make TIC10 using that information.

Although the original TIC10 research team had seemingly confirmed the predicted structure with mass spectrometry, no one had published a thorough characterization of the TIC10 molecule.

“There were no nuclear magnetic resonance data or X-ray crystallography data, and there was definitely no procedure for the synthesis,” Dr Lockner said. “My background was chemistry, though, so I was able to find a way to synthesize it starting from simple compounds.”

Surprising inactivity

There was just one problem with Dr Lockner’s newly synthesized “TIC10.” When tested, it failed to induce TRAIL expression in cells, even at high doses.

“Of course, I was nervous,” Dr Lockner said. “As a chemist, you never want to make a mistake and give biologists the wrong material.”

To try and verify they had the right material, Dr Janda’s team obtained a sample of TIC10 directly from the NCI.

“When we got that sample and tested it, we saw that it had the expected TRAIL-upregulating effect,” said Nicholas Jacob, a graduate student in the Janda Lab and coauthor of the new paper.

“That prompted us to look more closely at the structures of these 2 compounds.”

The researchers spent months characterizing their own synthesized material and the NCI material, using an array of sophisticated structural analysis tools. They also tested the 2 compounds’ biological effects.

The team eventually concluded that the TIC10 compound from the NCI library does boost TRAIL production in cells and remains promising as the basis for anticancer therapies, but it does not have the structure that was originally published.

The right structure

The originally published structure has a core made of 3 carbon-nitrogen rings in a straight line and does not induce TRAIL activity. The correct, TRAIL-inducing structure differs subtly, with an end ring that sticks out at an angle.

In chemists’ parlance, the 2 compounds are constitutional isomers: a linear imidazolinopyrimidinone and an angular imidazolinopyrimidinone.

And Dr Lockner found that the angular, TRAIL-inducing structure was easier to synthesize than the one originally described.

Now, with the correct molecule in hand and a solid understanding of its structure and synthesis, Dr Janda and his team are moving forward with their original plan to study TIC10 in combination with TRAIL-resistance-thwarting molecules as an anticancer therapy.

The therapeutic implications of TIC10 may even go beyond cancer, according to the researchers. The angular core of the TRAIL-inducing molecule Dr Janda’s team discovered is a novel type of a biologically active structure, or pharmacophore, from which chemists may now be able to build a new class of candidate drugs, possibly for a variety of ailments.

Micrograph showing DLBCL

The US Food and Drug Administration (FDA) has granted orphan designation to selinexor (KPT-330) for the treatment of diffuse large B-cell lymphoma (DLBCL).

The drug elicited responses in patients with non-Hodgkin lymphoma (NHL), including DLBCL, in an ongoing phase 1 study.

Selinexor is a selective inhibitor of nuclear transport that functions by binding to the nuclear export protein XPO1 (also called CRM1). This leads to the accumulation of tumor suppressor proteins in the cell nucleus, which is thought to cause apoptosis in cancer cells while largely sparing normal cells.

The FDA grants orphan designation to promote the development of drugs that target conditions affecting 200,000 or fewer US patients annually and are expected to provide significant therapeutic advantage over existing treatments.

Selinexor’s orphan designation for DLBCL qualifies the drug’s developer, Karyopharm Therapeutics, Inc., for benefits that apply across all stages of development, including an accelerated approval process, 7 years of market exclusivity following marketing approval, tax credits on US clinical trials, eligibility for orphan drug grants, and a waiver of certain administrative fees.

The FDA has also granted selinexor orphan status for the treatment of acute myeloid leukemia.

Phase 1 study

Researchers evaluated selinexor in an ongoing phase 1 study of patients with NHL or chronic lymphocytic leukemia (CLL) and presented results at the 2013 ASH Annual Meeting (abstract 90).

At that time, the study included 18 patients with NHL or CLL. They had a median age of 66.5 years and had received a median of 4.5 prior treatment regimens.

Patients received selinexor at 6 different dose levels. There were no clinically significant cumulative toxicities or cases of major organ dysfunction, and the maximum-tolerated dose was not reached. Researchers continued dosing at 35 mg/m² twice weekly.

Ten patients experienced drug-related grade 3/4 adverse events, including thrombocytopenia without bleeding (n=6), neutropenia (n=5), dehydration (n=1), syncope (n=1), hypotension (n=1), and fatigue (n=1).

The most common grade 1/2 events were anorexia (n=10), fatigue (n=9), diarrhea (n=6), vomiting (n=6), neutropenia (n=5), malaise (n=3), anemia (n=3), and weight loss (n=3).

Response was evaluable in 15 patients. Eighty percent of patients, all of whom had progressive disease on study entry, experienced tumor shrinkage or disease stabilization on selinexor. The other 20% of patients progressed.

Of 3 patients with DLBCL, 1 progressed, 1 had stable disease, and 1 achieved 93% tumor shrinkage.

“We are encouraged by the response data in patients with DLBCL who have received selinexor in our ongoing phase 1 clinical trial in advanced hematological malignancies,” said Michael G. Kauffman, MD, PhD, Karyopharm’s Chief Executive Officer.

“We plan to present updated clinical data for selinexor across multiple indications, including DLBCL, at ASCO 2014.”

Micrograph showing DLBCL

The US Food and Drug Administration (FDA) has granted orphan designation to selinexor (KPT-330) for the treatment of diffuse large B-cell lymphoma (DLBCL).

The drug elicited responses in patients with non-Hodgkin lymphoma (NHL), including DLBCL, in an ongoing phase 1 study.

Selinexor is a selective inhibitor of nuclear transport that functions by binding to the nuclear export protein XPO1 (also called CRM1). This leads to the accumulation of tumor suppressor proteins in the cell nucleus, which is thought to cause apoptosis in cancer cells while largely sparing normal cells.

The FDA grants orphan designation to promote the development of drugs that target conditions affecting 200,000 or fewer US patients annually and are expected to provide significant therapeutic advantage over existing treatments.

Selinexor’s orphan designation for DLBCL qualifies the drug’s developer, Karyopharm Therapeutics, Inc., for benefits that apply across all stages of development, including an accelerated approval process, 7 years of market exclusivity following marketing approval, tax credits on US clinical trials, eligibility for orphan drug grants, and a waiver of certain administrative fees.

The FDA has also granted selinexor orphan status for the treatment of acute myeloid leukemia.

Phase 1 study

Researchers evaluated selinexor in an ongoing phase 1 study of patients with NHL or chronic lymphocytic leukemia (CLL) and presented results at the 2013 ASH Annual Meeting (abstract 90).

At that time, the study included 18 patients with NHL or CLL. They had a median age of 66.5 years and had received a median of 4.5 prior treatment regimens.

Patients received selinexor at 6 different dose levels. There were no clinically significant cumulative toxicities or cases of major organ dysfunction, and the maximum-tolerated dose was not reached. Researchers continued dosing at 35 mg/m² twice weekly.

Ten patients experienced drug-related grade 3/4 adverse events, including thrombocytopenia without bleeding (n=6), neutropenia (n=5), dehydration (n=1), syncope (n=1), hypotension (n=1), and fatigue (n=1).

The most common grade 1/2 events were anorexia (n=10), fatigue (n=9), diarrhea (n=6), vomiting (n=6), neutropenia (n=5), malaise (n=3), anemia (n=3), and weight loss (n=3).

Response was evaluable in 15 patients. Eighty percent of patients, all of whom had progressive disease on study entry, experienced tumor shrinkage or disease stabilization on selinexor. The other 20% of patients progressed.

Of 3 patients with DLBCL, 1 progressed, 1 had stable disease, and 1 achieved 93% tumor shrinkage.

“We are encouraged by the response data in patients with DLBCL who have received selinexor in our ongoing phase 1 clinical trial in advanced hematological malignancies,” said Michael G. Kauffman, MD, PhD, Karyopharm’s Chief Executive Officer.

“We plan to present updated clinical data for selinexor across multiple indications, including DLBCL, at ASCO 2014.”

Micrograph showing DLBCL

The US Food and Drug Administration (FDA) has granted orphan designation to selinexor (KPT-330) for the treatment of diffuse large B-cell lymphoma (DLBCL).

The drug elicited responses in patients with non-Hodgkin lymphoma (NHL), including DLBCL, in an ongoing phase 1 study.

Selinexor is a selective inhibitor of nuclear transport that functions by binding to the nuclear export protein XPO1 (also called CRM1). This leads to the accumulation of tumor suppressor proteins in the cell nucleus, which is thought to cause apoptosis in cancer cells while largely sparing normal cells.

The FDA grants orphan designation to promote the development of drugs that target conditions affecting 200,000 or fewer US patients annually and are expected to provide significant therapeutic advantage over existing treatments.

Selinexor’s orphan designation for DLBCL qualifies the drug’s developer, Karyopharm Therapeutics, Inc., for benefits that apply across all stages of development, including an accelerated approval process, 7 years of market exclusivity following marketing approval, tax credits on US clinical trials, eligibility for orphan drug grants, and a waiver of certain administrative fees.

The FDA has also granted selinexor orphan status for the treatment of acute myeloid leukemia.

Phase 1 study

Researchers evaluated selinexor in an ongoing phase 1 study of patients with NHL or chronic lymphocytic leukemia (CLL) and presented results at the 2013 ASH Annual Meeting (abstract 90).

At that time, the study included 18 patients with NHL or CLL. They had a median age of 66.5 years and had received a median of 4.5 prior treatment regimens.

Patients received selinexor at 6 different dose levels. There were no clinically significant cumulative toxicities or cases of major organ dysfunction, and the maximum-tolerated dose was not reached. Researchers continued dosing at 35 mg/m² twice weekly.

Ten patients experienced drug-related grade 3/4 adverse events, including thrombocytopenia without bleeding (n=6), neutropenia (n=5), dehydration (n=1), syncope (n=1), hypotension (n=1), and fatigue (n=1).

The most common grade 1/2 events were anorexia (n=10), fatigue (n=9), diarrhea (n=6), vomiting (n=6), neutropenia (n=5), malaise (n=3), anemia (n=3), and weight loss (n=3).

Response was evaluable in 15 patients. Eighty percent of patients, all of whom had progressive disease on study entry, experienced tumor shrinkage or disease stabilization on selinexor. The other 20% of patients progressed.

Of 3 patients with DLBCL, 1 progressed, 1 had stable disease, and 1 achieved 93% tumor shrinkage.

“We are encouraged by the response data in patients with DLBCL who have received selinexor in our ongoing phase 1 clinical trial in advanced hematological malignancies,” said Michael G. Kauffman, MD, PhD, Karyopharm’s Chief Executive Officer.

“We plan to present updated clinical data for selinexor across multiple indications, including DLBCL, at ASCO 2014.”

Cancer patient receives therapy

Credit: Rhoda Baer

A review of clinical trial data from 2012 suggests Hispanic patients are underrepresented in US cancer studies, and many trial publications fail to provide information on patients’ racial/ethnic backgrounds.

Researchers analyzed 159 reports of phase 2 and 3 trials and found that roughly 21% included information on the number of minority patients enrolled.

About 8% of the publications included data on the number of Hispanic patients enrolled.

And from this data, the investigators found the accrual rate for Hispanic patients was about 4%.

According to the researchers, this lack of information and low representation inhibits physicians’ ability to provide optimal treatment to Hispanic cancer patients and patients belonging to other minority groups.

“We have a major responsibility to ensure adequate representation,” said study author Ian M. Thompson Jr, MD, of The University of Texas Health Science Center at San Antonio.

“How else will we know how best to treat our patients, and how else are we going to reduce the health disparities in [the Hispanic] population?”

Dr Thompson and his colleagues have a particular interest in the Hispanic population because 58% of San Antonio residents are Hispanic, as are 68% of residents in South Texas as a whole.

So the investigators wanted to determine Hispanic accrual rates in randomized trials of cancer patients. The team evaluated data from phase 2 and 3 cancer trials published in 2012. They focused on studies that were considered likely to change the standard of care and were published in “high-impact” journals.

The researchers identified 159 trials—68 phase 2 studies and 91 phase 3 studies. They discovered that 33 of the trial publications—about 21%—disclosed data on minority accrual. And 13 publications—about 8%—included data on the accrual of Hispanic cancer patients.

Of the 4154 patients enrolled on those 13 trials, 162 were Hispanic, which translates to an overall accrual rate of 3.9%. The enrollment of Hispanic patients ranged from 1 patient (0.5%) in a phase 2 trial of lung cancer to 17 patients (26%) in a phase 2 study of acute lymphoblastic leukemia.

“Fundamentally, in the most recent published cancer clinical trials, either the number and proportion of Hispanics are not reported or are far below their actual representation in the national population,” Dr Thompson summarized.

“For institutions like ours that serve a ‘minority-majority’ population, it’s a major responsibility for us to ensure adequate representation so that we can tell our patients how they can best be treated and how we can reduce the disparities of this rapidly growing population.”

Dr Thompson and his colleagues described this research in the Journal of Clinical Oncology.

Cancer patient receives therapy

Credit: Rhoda Baer

A review of clinical trial data from 2012 suggests Hispanic patients are underrepresented in US cancer studies, and many trial publications fail to provide information on patients’ racial/ethnic backgrounds.

Researchers analyzed 159 reports of phase 2 and 3 trials and found that roughly 21% included information on the number of minority patients enrolled.

About 8% of the publications included data on the number of Hispanic patients enrolled.

And from this data, the investigators found the accrual rate for Hispanic patients was about 4%.

According to the researchers, this lack of information and low representation inhibits physicians’ ability to provide optimal treatment to Hispanic cancer patients and patients belonging to other minority groups.

“We have a major responsibility to ensure adequate representation,” said study author Ian M. Thompson Jr, MD, of The University of Texas Health Science Center at San Antonio.

“How else will we know how best to treat our patients, and how else are we going to reduce the health disparities in [the Hispanic] population?”

Dr Thompson and his colleagues have a particular interest in the Hispanic population because 58% of San Antonio residents are Hispanic, as are 68% of residents in South Texas as a whole.

So the investigators wanted to determine Hispanic accrual rates in randomized trials of cancer patients. The team evaluated data from phase 2 and 3 cancer trials published in 2012. They focused on studies that were considered likely to change the standard of care and were published in “high-impact” journals.

The researchers identified 159 trials—68 phase 2 studies and 91 phase 3 studies. They discovered that 33 of the trial publications—about 21%—disclosed data on minority accrual. And 13 publications—about 8%—included data on the accrual of Hispanic cancer patients.

Of the 4154 patients enrolled on those 13 trials, 162 were Hispanic, which translates to an overall accrual rate of 3.9%. The enrollment of Hispanic patients ranged from 1 patient (0.5%) in a phase 2 trial of lung cancer to 17 patients (26%) in a phase 2 study of acute lymphoblastic leukemia.

“Fundamentally, in the most recent published cancer clinical trials, either the number and proportion of Hispanics are not reported or are far below their actual representation in the national population,” Dr Thompson summarized.

“For institutions like ours that serve a ‘minority-majority’ population, it’s a major responsibility for us to ensure adequate representation so that we can tell our patients how they can best be treated and how we can reduce the disparities of this rapidly growing population.”

Dr Thompson and his colleagues described this research in the Journal of Clinical Oncology.

Cancer patient receives therapy

Credit: Rhoda Baer

A review of clinical trial data from 2012 suggests Hispanic patients are underrepresented in US cancer studies, and many trial publications fail to provide information on patients’ racial/ethnic backgrounds.

Researchers analyzed 159 reports of phase 2 and 3 trials and found that roughly 21% included information on the number of minority patients enrolled.

About 8% of the publications included data on the number of Hispanic patients enrolled.

And from this data, the investigators found the accrual rate for Hispanic patients was about 4%.

According to the researchers, this lack of information and low representation inhibits physicians’ ability to provide optimal treatment to Hispanic cancer patients and patients belonging to other minority groups.

“We have a major responsibility to ensure adequate representation,” said study author Ian M. Thompson Jr, MD, of The University of Texas Health Science Center at San Antonio.

“How else will we know how best to treat our patients, and how else are we going to reduce the health disparities in [the Hispanic] population?”

Dr Thompson and his colleagues have a particular interest in the Hispanic population because 58% of San Antonio residents are Hispanic, as are 68% of residents in South Texas as a whole.

So the investigators wanted to determine Hispanic accrual rates in randomized trials of cancer patients. The team evaluated data from phase 2 and 3 cancer trials published in 2012. They focused on studies that were considered likely to change the standard of care and were published in “high-impact” journals.

The researchers identified 159 trials—68 phase 2 studies and 91 phase 3 studies. They discovered that 33 of the trial publications—about 21%—disclosed data on minority accrual. And 13 publications—about 8%—included data on the accrual of Hispanic cancer patients.

Of the 4154 patients enrolled on those 13 trials, 162 were Hispanic, which translates to an overall accrual rate of 3.9%. The enrollment of Hispanic patients ranged from 1 patient (0.5%) in a phase 2 trial of lung cancer to 17 patients (26%) in a phase 2 study of acute lymphoblastic leukemia.

“Fundamentally, in the most recent published cancer clinical trials, either the number and proportion of Hispanics are not reported or are far below their actual representation in the national population,” Dr Thompson summarized.

“For institutions like ours that serve a ‘minority-majority’ population, it’s a major responsibility for us to ensure adequate representation so that we can tell our patients how they can best be treated and how we can reduce the disparities of this rapidly growing population.”

Dr Thompson and his colleagues described this research in the Journal of Clinical Oncology.

Monoclonal antibodies

Credit: Linda Bartlett

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for elotuzumab, a humanized monoclonal antibody

(mAb).

The designation is for elotuzumab used in combination with lenalidomide and dexamethasone to treat patients with multiple myeloma (MM) who have received 1 or more prior therapies.

The FDA’s decision is based on findings from a phase 2 trial in which MM patients received that treatment combination.

According to the FDA, breakthrough designation is intended to expedite the development and review of drugs for serious or life-threatening conditions. For a treatment to receive this designation, there must be preliminary clinical evidence that demonstrates the drug may offer substantial improvement over currently available therapy on at least 1 clinically significant endpoint.

About elotuzumab

Elotuzumab is a humanized IgG1 mAb targeting signaling lymphocyte activation molecule (SLAMF7, also known as CS1), a glycoprotein expressed on myeloma and natural killer cells but not detectable in normal tissue.

Researchers are investigating whether, through both direct activation and engagement of natural killer cells, elotuzumab may selectively target and kill SLAMF7-expressing myeloma cells.

Elotuzumab is under investigation as a monotherapy in smoldering myeloma and in combination with other therapies in first-line and relapsed or refractory MM.

A clinical development program for the mAb is underway, including phase 3 trials in first-line MM (ELOQUENT-1) and relapsed or refractory MM (ELOQUENT-2). The agent is also under investigation in a randomized, phase 2 study of bortezomib and dexamethasone in patients with relapsed or refractory MM.

Elotuzumab is under development by AbbVie and Bristol-Myers Squibb.

Phase 2 trial results

The breakthrough therapy designation for elotuzumab is based on results of a randomized, phase 2 trial presented at the EHA 2013 Annual Congress (abstract 14). Study investigators tested 2 doses of the mAb in combination with lenalidomide and low-dose dexamethasone in patients with previously treated MM.

Patients were randomized 1:1 to receive elotuzumab at 10 mg/kg or 20 mg/kg (intravenous infusion on days 1, 8, 15, and 22 of a 28-day cycle in the first 2 cycles and then days 1 and 15 of subsequent cycles) in combination with oral lenalidomide at 25 mg/day on days 1 to 21 and oral dexamethasone at 40 mg/week. Patients were treated until their disease progressed or they developed unacceptable toxicity.

In the 10 mg/kg arm (n=36), which is the dose used in the ongoing phase 3 trials, the median progression-free survival was 33 months, after a median follow-up of 20.8 months. And the objective response rate was 92%.

In the 20 mg/kg arm (n=37), the median progression-free survival was 18 months, after a median follow-up of 17.1 months. And the objective response rate was 76%.

The safety data were consistent with previously reported results for elotuzumab from this trial. In patients receiving elotuzumab at 10 mg/kg or 20 mg/kg, most treatment-emergent adverse events occurred within 18 months of starting therapy.

The most common grade 3/4 adverse events for the 10 mg/kg and 20 mg/kg arms, respectively, were lymphopenia (26% and 9%), neutropenia (21% and 22%), thrombocytopenia (21% and 17%), anemia (13% and 12%), leukopenia (8% and 7%), hyperglycemia (5% and 12%), pneumonia (8% and 5%), diarrhea (10% and 5%), fatigue (8% and 9%), and hypokalemia (8% and 5%).

Two deaths occurred on study. One patient died of pneumonia, multiple organ failure, and sepsis. The other died of disease progression.

Monoclonal antibodies

Credit: Linda Bartlett

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for elotuzumab, a humanized monoclonal antibody

(mAb).

The designation is for elotuzumab used in combination with lenalidomide and dexamethasone to treat patients with multiple myeloma (MM) who have received 1 or more prior therapies.

The FDA’s decision is based on findings from a phase 2 trial in which MM patients received that treatment combination.

According to the FDA, breakthrough designation is intended to expedite the development and review of drugs for serious or life-threatening conditions. For a treatment to receive this designation, there must be preliminary clinical evidence that demonstrates the drug may offer substantial improvement over currently available therapy on at least 1 clinically significant endpoint.

About elotuzumab

Elotuzumab is a humanized IgG1 mAb targeting signaling lymphocyte activation molecule (SLAMF7, also known as CS1), a glycoprotein expressed on myeloma and natural killer cells but not detectable in normal tissue.

Researchers are investigating whether, through both direct activation and engagement of natural killer cells, elotuzumab may selectively target and kill SLAMF7-expressing myeloma cells.

Elotuzumab is under investigation as a monotherapy in smoldering myeloma and in combination with other therapies in first-line and relapsed or refractory MM.

A clinical development program for the mAb is underway, including phase 3 trials in first-line MM (ELOQUENT-1) and relapsed or refractory MM (ELOQUENT-2). The agent is also under investigation in a randomized, phase 2 study of bortezomib and dexamethasone in patients with relapsed or refractory MM.

Elotuzumab is under development by AbbVie and Bristol-Myers Squibb.

Phase 2 trial results

The breakthrough therapy designation for elotuzumab is based on results of a randomized, phase 2 trial presented at the EHA 2013 Annual Congress (abstract 14). Study investigators tested 2 doses of the mAb in combination with lenalidomide and low-dose dexamethasone in patients with previously treated MM.

Patients were randomized 1:1 to receive elotuzumab at 10 mg/kg or 20 mg/kg (intravenous infusion on days 1, 8, 15, and 22 of a 28-day cycle in the first 2 cycles and then days 1 and 15 of subsequent cycles) in combination with oral lenalidomide at 25 mg/day on days 1 to 21 and oral dexamethasone at 40 mg/week. Patients were treated until their disease progressed or they developed unacceptable toxicity.

In the 10 mg/kg arm (n=36), which is the dose used in the ongoing phase 3 trials, the median progression-free survival was 33 months, after a median follow-up of 20.8 months. And the objective response rate was 92%.

In the 20 mg/kg arm (n=37), the median progression-free survival was 18 months, after a median follow-up of 17.1 months. And the objective response rate was 76%.

The safety data were consistent with previously reported results for elotuzumab from this trial. In patients receiving elotuzumab at 10 mg/kg or 20 mg/kg, most treatment-emergent adverse events occurred within 18 months of starting therapy.

The most common grade 3/4 adverse events for the 10 mg/kg and 20 mg/kg arms, respectively, were lymphopenia (26% and 9%), neutropenia (21% and 22%), thrombocytopenia (21% and 17%), anemia (13% and 12%), leukopenia (8% and 7%), hyperglycemia (5% and 12%), pneumonia (8% and 5%), diarrhea (10% and 5%), fatigue (8% and 9%), and hypokalemia (8% and 5%).

Two deaths occurred on study. One patient died of pneumonia, multiple organ failure, and sepsis. The other died of disease progression.

Monoclonal antibodies

Credit: Linda Bartlett

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for elotuzumab, a humanized monoclonal antibody

(mAb).

The designation is for elotuzumab used in combination with lenalidomide and dexamethasone to treat patients with multiple myeloma (MM) who have received 1 or more prior therapies.

The FDA’s decision is based on findings from a phase 2 trial in which MM patients received that treatment combination.

According to the FDA, breakthrough designation is intended to expedite the development and review of drugs for serious or life-threatening conditions. For a treatment to receive this designation, there must be preliminary clinical evidence that demonstrates the drug may offer substantial improvement over currently available therapy on at least 1 clinically significant endpoint.

About elotuzumab

Elotuzumab is a humanized IgG1 mAb targeting signaling lymphocyte activation molecule (SLAMF7, also known as CS1), a glycoprotein expressed on myeloma and natural killer cells but not detectable in normal tissue.

Researchers are investigating whether, through both direct activation and engagement of natural killer cells, elotuzumab may selectively target and kill SLAMF7-expressing myeloma cells.

Elotuzumab is under investigation as a monotherapy in smoldering myeloma and in combination with other therapies in first-line and relapsed or refractory MM.

A clinical development program for the mAb is underway, including phase 3 trials in first-line MM (ELOQUENT-1) and relapsed or refractory MM (ELOQUENT-2). The agent is also under investigation in a randomized, phase 2 study of bortezomib and dexamethasone in patients with relapsed or refractory MM.

Elotuzumab is under development by AbbVie and Bristol-Myers Squibb.

Phase 2 trial results

The breakthrough therapy designation for elotuzumab is based on results of a randomized, phase 2 trial presented at the EHA 2013 Annual Congress (abstract 14). Study investigators tested 2 doses of the mAb in combination with lenalidomide and low-dose dexamethasone in patients with previously treated MM.

Patients were randomized 1:1 to receive elotuzumab at 10 mg/kg or 20 mg/kg (intravenous infusion on days 1, 8, 15, and 22 of a 28-day cycle in the first 2 cycles and then days 1 and 15 of subsequent cycles) in combination with oral lenalidomide at 25 mg/day on days 1 to 21 and oral dexamethasone at 40 mg/week. Patients were treated until their disease progressed or they developed unacceptable toxicity.

In the 10 mg/kg arm (n=36), which is the dose used in the ongoing phase 3 trials, the median progression-free survival was 33 months, after a median follow-up of 20.8 months. And the objective response rate was 92%.

In the 20 mg/kg arm (n=37), the median progression-free survival was 18 months, after a median follow-up of 17.1 months. And the objective response rate was 76%.

The safety data were consistent with previously reported results for elotuzumab from this trial. In patients receiving elotuzumab at 10 mg/kg or 20 mg/kg, most treatment-emergent adverse events occurred within 18 months of starting therapy.

The most common grade 3/4 adverse events for the 10 mg/kg and 20 mg/kg arms, respectively, were lymphopenia (26% and 9%), neutropenia (21% and 22%), thrombocytopenia (21% and 17%), anemia (13% and 12%), leukopenia (8% and 7%), hyperglycemia (5% and 12%), pneumonia (8% and 5%), diarrhea (10% and 5%), fatigue (8% and 9%), and hypokalemia (8% and 5%).

Two deaths occurred on study. One patient died of pneumonia, multiple organ failure, and sepsis. The other died of disease progression.

The somatostatin analogue pasireotide reduced postoperative pancreatic fistula leak or abscess by 56%, compared with placebo, a randomized study has determined.

Pasireotide (Signifor) was effective after both pancreaticoduodenectomy and distal pancreatectomy, whether or not the pancreatic duct was dilated, Dr. Peter J. Allen and his colleagues wrote in the May 21 issue of the New England Journal of Medicine (N. Engl. J. Med. 2014;370:2014-22).

In those patients who did develop fistulas or leaks, pasireotide was associated with fewer grade 3 occurrences.

"These results suggest that ... not only were many leaks and fistulas prevented, but when they did occur they were less clinically relevant," wrote Dr. Allen of the Memorial Sloan Kettering Cancer Center, New York, and his coauthors.

The study randomized 300 patients to subcutaneous injections of either placebo or pasireotide twice daily for 7 days after pancreatic surgery. The primary endpoint was the development of a pancreatic leak, fistula, or abscess of at least grade 3. Secondary endpoints included the overall rate of pancreatic complications (all grades) and the rate of grade B or grade C pancreatic fistula.

Patients were a mean of 64 years old. Most (73%) underwent a pancreaticoduodenectomy. The average length of stay for these patients was about 10 days. The active group received 900 mcg of pasireotide subcutaneously twice daily for 7 days, beginning on the morning of surgery.

Mean postoperative serum glucose levels were significantly higher in patients taking pasireotide (258 mg/dL vs. 215 mg/dL). Readmission occurred in significantly fewer pasireotide patients (17% vs. 29%).

Significantly fewer of those taking the active drug were able to finish the entire course of 14 doses (76% vs. 86% given placebo). The lower completion rate was mostly due to nausea and vomiting, which caused 26 patients in the active group and 3 in the placebo group to withdraw from the study.

A leak or fistula of grade 3 or higher developed in 45 patients. The outcome was significantly less common among those taking pasireotide than among those on placebo (9% vs. 21%; relative risk, 0.44). "This corresponded to an absolute risk reduction of 11.7 percentage points," with a number needed to treat of 8, the investigators said.

Pasireotide was significantly more effective than placebo in surgical subgroups, including pancreaticoduodenectomy (RR, 0.49) and distal pancreatectomy (RR, 0.32). The effect was also positive whether the pancreatic duct was dilated (RR, 0.11) or nondilated (RR, 0.55).

The secondary outcome (grade B or C postoperative fistula) occurred in 37 patients (12%). In the pasireotide group, there were 12 grade B fistulas and no grade C fistulas. In the placebo group, there were 20 grade B and 5 grade C fistulas.

Overall 60-day mortality was 0.7% (one death in each treatment group). Grade 3 and 4 complications were common, occurring in 92% of the pasireotide group and 90% of the placebo group. Most of these were expected postoperative serum abnormalities.

The investigators said that the other approved somatostatin analogue, octreotide, has not been clearly associated with pancreatic leak reduction. They suggested that pasireotide may be more effective because it has a longer half-life and binds to four of the five somatostatin-receptor subtypes, rather than just two, as octreotide does.

They added that the octreotide studies were conducted before 2005, when there was no consistent definition of postoperative pancreatic fistula. Therefore, they concluded, the extant data cannot be used to identify octreotide efficacy in this application.

Pasireotide, which is made by Novartis Pharmaceuticals, is currently approved as an injection for the treatment of Cushing’s disease patients who cannot be helped through surgery.

Novartis Pharmaceuticals sponsored the trial. Dr. Allen received Novartis grant funding but had no other financial ties with the company.

[email protected]

The somatostatin analogue pasireotide reduced postoperative pancreatic fistula leak or abscess by 56%, compared with placebo, a randomized study has determined.

Pasireotide (Signifor) was effective after both pancreaticoduodenectomy and distal pancreatectomy, whether or not the pancreatic duct was dilated, Dr. Peter J. Allen and his colleagues wrote in the May 21 issue of the New England Journal of Medicine (N. Engl. J. Med. 2014;370:2014-22).

In those patients who did develop fistulas or leaks, pasireotide was associated with fewer grade 3 occurrences.

"These results suggest that ... not only were many leaks and fistulas prevented, but when they did occur they were less clinically relevant," wrote Dr. Allen of the Memorial Sloan Kettering Cancer Center, New York, and his coauthors.

The study randomized 300 patients to subcutaneous injections of either placebo or pasireotide twice daily for 7 days after pancreatic surgery. The primary endpoint was the development of a pancreatic leak, fistula, or abscess of at least grade 3. Secondary endpoints included the overall rate of pancreatic complications (all grades) and the rate of grade B or grade C pancreatic fistula.

Patients were a mean of 64 years old. Most (73%) underwent a pancreaticoduodenectomy. The average length of stay for these patients was about 10 days. The active group received 900 mcg of pasireotide subcutaneously twice daily for 7 days, beginning on the morning of surgery.

Mean postoperative serum glucose levels were significantly higher in patients taking pasireotide (258 mg/dL vs. 215 mg/dL). Readmission occurred in significantly fewer pasireotide patients (17% vs. 29%).

Significantly fewer of those taking the active drug were able to finish the entire course of 14 doses (76% vs. 86% given placebo). The lower completion rate was mostly due to nausea and vomiting, which caused 26 patients in the active group and 3 in the placebo group to withdraw from the study.

A leak or fistula of grade 3 or higher developed in 45 patients. The outcome was significantly less common among those taking pasireotide than among those on placebo (9% vs. 21%; relative risk, 0.44). "This corresponded to an absolute risk reduction of 11.7 percentage points," with a number needed to treat of 8, the investigators said.

Pasireotide was significantly more effective than placebo in surgical subgroups, including pancreaticoduodenectomy (RR, 0.49) and distal pancreatectomy (RR, 0.32). The effect was also positive whether the pancreatic duct was dilated (RR, 0.11) or nondilated (RR, 0.55).

The secondary outcome (grade B or C postoperative fistula) occurred in 37 patients (12%). In the pasireotide group, there were 12 grade B fistulas and no grade C fistulas. In the placebo group, there were 20 grade B and 5 grade C fistulas.

Overall 60-day mortality was 0.7% (one death in each treatment group). Grade 3 and 4 complications were common, occurring in 92% of the pasireotide group and 90% of the placebo group. Most of these were expected postoperative serum abnormalities.

The investigators said that the other approved somatostatin analogue, octreotide, has not been clearly associated with pancreatic leak reduction. They suggested that pasireotide may be more effective because it has a longer half-life and binds to four of the five somatostatin-receptor subtypes, rather than just two, as octreotide does.

They added that the octreotide studies were conducted before 2005, when there was no consistent definition of postoperative pancreatic fistula. Therefore, they concluded, the extant data cannot be used to identify octreotide efficacy in this application.

Pasireotide, which is made by Novartis Pharmaceuticals, is currently approved as an injection for the treatment of Cushing’s disease patients who cannot be helped through surgery.

Novartis Pharmaceuticals sponsored the trial. Dr. Allen received Novartis grant funding but had no other financial ties with the company.

[email protected]

The somatostatin analogue pasireotide reduced postoperative pancreatic fistula leak or abscess by 56%, compared with placebo, a randomized study has determined.

Pasireotide (Signifor) was effective after both pancreaticoduodenectomy and distal pancreatectomy, whether or not the pancreatic duct was dilated, Dr. Peter J. Allen and his colleagues wrote in the May 21 issue of the New England Journal of Medicine (N. Engl. J. Med. 2014;370:2014-22).

In those patients who did develop fistulas or leaks, pasireotide was associated with fewer grade 3 occurrences.

"These results suggest that ... not only were many leaks and fistulas prevented, but when they did occur they were less clinically relevant," wrote Dr. Allen of the Memorial Sloan Kettering Cancer Center, New York, and his coauthors.

The study randomized 300 patients to subcutaneous injections of either placebo or pasireotide twice daily for 7 days after pancreatic surgery. The primary endpoint was the development of a pancreatic leak, fistula, or abscess of at least grade 3. Secondary endpoints included the overall rate of pancreatic complications (all grades) and the rate of grade B or grade C pancreatic fistula.

Patients were a mean of 64 years old. Most (73%) underwent a pancreaticoduodenectomy. The average length of stay for these patients was about 10 days. The active group received 900 mcg of pasireotide subcutaneously twice daily for 7 days, beginning on the morning of surgery.

Mean postoperative serum glucose levels were significantly higher in patients taking pasireotide (258 mg/dL vs. 215 mg/dL). Readmission occurred in significantly fewer pasireotide patients (17% vs. 29%).

Significantly fewer of those taking the active drug were able to finish the entire course of 14 doses (76% vs. 86% given placebo). The lower completion rate was mostly due to nausea and vomiting, which caused 26 patients in the active group and 3 in the placebo group to withdraw from the study.

A leak or fistula of grade 3 or higher developed in 45 patients. The outcome was significantly less common among those taking pasireotide than among those on placebo (9% vs. 21%; relative risk, 0.44). "This corresponded to an absolute risk reduction of 11.7 percentage points," with a number needed to treat of 8, the investigators said.

Pasireotide was significantly more effective than placebo in surgical subgroups, including pancreaticoduodenectomy (RR, 0.49) and distal pancreatectomy (RR, 0.32). The effect was also positive whether the pancreatic duct was dilated (RR, 0.11) or nondilated (RR, 0.55).

The secondary outcome (grade B or C postoperative fistula) occurred in 37 patients (12%). In the pasireotide group, there were 12 grade B fistulas and no grade C fistulas. In the placebo group, there were 20 grade B and 5 grade C fistulas.

Overall 60-day mortality was 0.7% (one death in each treatment group). Grade 3 and 4 complications were common, occurring in 92% of the pasireotide group and 90% of the placebo group. Most of these were expected postoperative serum abnormalities.

The investigators said that the other approved somatostatin analogue, octreotide, has not been clearly associated with pancreatic leak reduction. They suggested that pasireotide may be more effective because it has a longer half-life and binds to four of the five somatostatin-receptor subtypes, rather than just two, as octreotide does.

They added that the octreotide studies were conducted before 2005, when there was no consistent definition of postoperative pancreatic fistula. Therefore, they concluded, the extant data cannot be used to identify octreotide efficacy in this application.

Pasireotide, which is made by Novartis Pharmaceuticals, is currently approved as an injection for the treatment of Cushing’s disease patients who cannot be helped through surgery.

Novartis Pharmaceuticals sponsored the trial. Dr. Allen received Novartis grant funding but had no other financial ties with the company.

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Patients diagnosed with Middle East Respiratory Syndrome (MERS) in Indiana and Florida have healthcare workers and hospitalists on the lookout for additional cases of the potentially fatal respiratory infection.

Hospitalists should pay attention to patients exhibiting fever and respiratory symptoms who traveled to the Arabian Peninsula in the 14 days prior to disease onset, and contact the hospital epidemiologist if MERS is suspected, says James Pile, MD, vice chair of the department of hospital medicine at the Cleveland Clinic.

The CDC has reported three cases of MERS this month. The first, reported on May 2, involved a healthcare worker from Saudi Arabia who traveled to Indiana to visit family. The second was reported on May 11, when another visiting healthcare worker from Saudi Arabia checked into the emergency department in Orlando, Fla., after he fell ill with fever, chills, and a slight cough. Both patients are considered to be fully recovered.

The third MERS case is in an Illinois man who had a business meeting with the patient from Indiana and represents the first case of the virus being contracted in the U.S. A blood test confirmed that the Illinois man had been infected with the virus, but he’s reported that he no longer feels sick.

Caused by a coronavirus called MERS-CoV, MERS was first reported in Saudi Arabia in 2012. So far, there have been more than 600 confirmed cases around the world and 181 people have died, according to the World Health Organization.

"The CDC suggests that the index U.S. case represents a very low threat to the general population in this country, and my sense is that that this will not turn out to be a major issue for the U.S. healthcare system, but there’s still a lot we don’t know about MERS," Dr. Pile says. “The scope of the issue should become much clearer over the next couple of months.”

For more information on MERS, check out this CDC fact sheet.

Read physician editor Danielle Scheurer's recent blog post on the MERS situation.

Visit our website for more information about hospitalists and infectious disease care.

Patients diagnosed with Middle East Respiratory Syndrome (MERS) in Indiana and Florida have healthcare workers and hospitalists on the lookout for additional cases of the potentially fatal respiratory infection.

Hospitalists should pay attention to patients exhibiting fever and respiratory symptoms who traveled to the Arabian Peninsula in the 14 days prior to disease onset, and contact the hospital epidemiologist if MERS is suspected, says James Pile, MD, vice chair of the department of hospital medicine at the Cleveland Clinic.

The CDC has reported three cases of MERS this month. The first, reported on May 2, involved a healthcare worker from Saudi Arabia who traveled to Indiana to visit family. The second was reported on May 11, when another visiting healthcare worker from Saudi Arabia checked into the emergency department in Orlando, Fla., after he fell ill with fever, chills, and a slight cough. Both patients are considered to be fully recovered.

The third MERS case is in an Illinois man who had a business meeting with the patient from Indiana and represents the first case of the virus being contracted in the U.S. A blood test confirmed that the Illinois man had been infected with the virus, but he’s reported that he no longer feels sick.

Caused by a coronavirus called MERS-CoV, MERS was first reported in Saudi Arabia in 2012. So far, there have been more than 600 confirmed cases around the world and 181 people have died, according to the World Health Organization.

"The CDC suggests that the index U.S. case represents a very low threat to the general population in this country, and my sense is that that this will not turn out to be a major issue for the U.S. healthcare system, but there’s still a lot we don’t know about MERS," Dr. Pile says. “The scope of the issue should become much clearer over the next couple of months.”

For more information on MERS, check out this CDC fact sheet.

Read physician editor Danielle Scheurer's recent blog post on the MERS situation.

Visit our website for more information about hospitalists and infectious disease care.

Patients diagnosed with Middle East Respiratory Syndrome (MERS) in Indiana and Florida have healthcare workers and hospitalists on the lookout for additional cases of the potentially fatal respiratory infection.

Hospitalists should pay attention to patients exhibiting fever and respiratory symptoms who traveled to the Arabian Peninsula in the 14 days prior to disease onset, and contact the hospital epidemiologist if MERS is suspected, says James Pile, MD, vice chair of the department of hospital medicine at the Cleveland Clinic.

The CDC has reported three cases of MERS this month. The first, reported on May 2, involved a healthcare worker from Saudi Arabia who traveled to Indiana to visit family. The second was reported on May 11, when another visiting healthcare worker from Saudi Arabia checked into the emergency department in Orlando, Fla., after he fell ill with fever, chills, and a slight cough. Both patients are considered to be fully recovered.

The third MERS case is in an Illinois man who had a business meeting with the patient from Indiana and represents the first case of the virus being contracted in the U.S. A blood test confirmed that the Illinois man had been infected with the virus, but he’s reported that he no longer feels sick.

Caused by a coronavirus called MERS-CoV, MERS was first reported in Saudi Arabia in 2012. So far, there have been more than 600 confirmed cases around the world and 181 people have died, according to the World Health Organization.

"The CDC suggests that the index U.S. case represents a very low threat to the general population in this country, and my sense is that that this will not turn out to be a major issue for the U.S. healthcare system, but there’s still a lot we don’t know about MERS," Dr. Pile says. “The scope of the issue should become much clearer over the next couple of months.”

For more information on MERS, check out this CDC fact sheet.

Read physician editor Danielle Scheurer's recent blog post on the MERS situation.

Visit our website for more information about hospitalists and infectious disease care.