STOCKHOLM – The good news about cognitive impairment in patients with multiple sclerosis who’ve been using cannabis heavily for symptom relief – even for many years – is that their memory, executive function, and information processing speed will improve significantly once they’ve been off the drug for just 28 days, according to the results of a randomized trial presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

“It’s good for neurologists to know that, if they prescribe cannabis or their patient is self-medicating and chooses to stop, their cognition will improve considerably,” observed Cecilia Meza, a coinvestigator in the study led by Anthony Feinstein, MD, professor of psychiatry at the University of Toronto.

But there’s a surprise twist to this study, she explained in an interview: “We showed patients their results, and they also felt that their cognition was doing a lot better, but despite that, they would rather be using cannabis to feel better than to have their memory intact. The pain was that bad,” said Ms. Meza, a research coordinator at the university’s Sunnybrook Research Institute.

It’s known that cognitive impairment in healthy long-term cannabis users, provided they started as adults, is fully reversed after 28 days of abstinence. But disease-related cognitive dysfunction affects 40%-80% of patients with MS, and cannabis use may compound this impairment. This Canadian study asked a previously unaddressed question: Does coming off cannabis make a difference cognitively in the MS population?

The study included 40 MS patients with global impairment of cognition, none of whom were cannabis users prior to their diagnosis. They typically started using it for MS symptom relief 2-3 years after receiving their diagnosis. By the time they were approached for study participation, they had been using cannabis four to five times per day or more for an average of 7 years for relief of symptoms, including incontinence, spasticity, poor sleep, headaches, and difficulties in eating.

All participants were willing to try 28 days of abstinence; half were randomized to do so, while the others stayed the course. Study endpoints included change from baseline to day 28 in the Brief Repeatable Neuropsychological Battery, functional MRI done while taking the Symbol Digit Modalities Test, and urine testing to assure compliance with abstinence.

By day 28, the abstinence group – and with one exception, urine testing confirmed they were bona fide cannabis quitters for the study duration – performed significantly better on the neuropsychological test battery than at baseline, with an associated significant increase in brain activation in the bilateral inferior frontal gyri, as well as the caudate and declive cerebellum while executing the Symbol Digit Modalities Test. The control group who kept on using cannabis showed no such improvements.

The full study details were published in conjunction with Ms. Meza’s presentation (Brain. 2019 Sep 1;142[9]:2800-12).

She reported having no financial conflicts regarding the study, funded by the Multiple Sclerosis Society of Canada.

[email protected]

SOURCE: Meza C. ECTRIMS 2019, Abstract P542.

STOCKHOLM – The good news about cognitive impairment in patients with multiple sclerosis who’ve been using cannabis heavily for symptom relief – even for many years – is that their memory, executive function, and information processing speed will improve significantly once they’ve been off the drug for just 28 days, according to the results of a randomized trial presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

“It’s good for neurologists to know that, if they prescribe cannabis or their patient is self-medicating and chooses to stop, their cognition will improve considerably,” observed Cecilia Meza, a coinvestigator in the study led by Anthony Feinstein, MD, professor of psychiatry at the University of Toronto.

But there’s a surprise twist to this study, she explained in an interview: “We showed patients their results, and they also felt that their cognition was doing a lot better, but despite that, they would rather be using cannabis to feel better than to have their memory intact. The pain was that bad,” said Ms. Meza, a research coordinator at the university’s Sunnybrook Research Institute.

It’s known that cognitive impairment in healthy long-term cannabis users, provided they started as adults, is fully reversed after 28 days of abstinence. But disease-related cognitive dysfunction affects 40%-80% of patients with MS, and cannabis use may compound this impairment. This Canadian study asked a previously unaddressed question: Does coming off cannabis make a difference cognitively in the MS population?

The study included 40 MS patients with global impairment of cognition, none of whom were cannabis users prior to their diagnosis. They typically started using it for MS symptom relief 2-3 years after receiving their diagnosis. By the time they were approached for study participation, they had been using cannabis four to five times per day or more for an average of 7 years for relief of symptoms, including incontinence, spasticity, poor sleep, headaches, and difficulties in eating.

All participants were willing to try 28 days of abstinence; half were randomized to do so, while the others stayed the course. Study endpoints included change from baseline to day 28 in the Brief Repeatable Neuropsychological Battery, functional MRI done while taking the Symbol Digit Modalities Test, and urine testing to assure compliance with abstinence.

By day 28, the abstinence group – and with one exception, urine testing confirmed they were bona fide cannabis quitters for the study duration – performed significantly better on the neuropsychological test battery than at baseline, with an associated significant increase in brain activation in the bilateral inferior frontal gyri, as well as the caudate and declive cerebellum while executing the Symbol Digit Modalities Test. The control group who kept on using cannabis showed no such improvements.

The full study details were published in conjunction with Ms. Meza’s presentation (Brain. 2019 Sep 1;142[9]:2800-12).

She reported having no financial conflicts regarding the study, funded by the Multiple Sclerosis Society of Canada.

[email protected]

SOURCE: Meza C. ECTRIMS 2019, Abstract P542.

STOCKHOLM – The good news about cognitive impairment in patients with multiple sclerosis who’ve been using cannabis heavily for symptom relief – even for many years – is that their memory, executive function, and information processing speed will improve significantly once they’ve been off the drug for just 28 days, according to the results of a randomized trial presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

“It’s good for neurologists to know that, if they prescribe cannabis or their patient is self-medicating and chooses to stop, their cognition will improve considerably,” observed Cecilia Meza, a coinvestigator in the study led by Anthony Feinstein, MD, professor of psychiatry at the University of Toronto.

But there’s a surprise twist to this study, she explained in an interview: “We showed patients their results, and they also felt that their cognition was doing a lot better, but despite that, they would rather be using cannabis to feel better than to have their memory intact. The pain was that bad,” said Ms. Meza, a research coordinator at the university’s Sunnybrook Research Institute.

It’s known that cognitive impairment in healthy long-term cannabis users, provided they started as adults, is fully reversed after 28 days of abstinence. But disease-related cognitive dysfunction affects 40%-80% of patients with MS, and cannabis use may compound this impairment. This Canadian study asked a previously unaddressed question: Does coming off cannabis make a difference cognitively in the MS population?

The study included 40 MS patients with global impairment of cognition, none of whom were cannabis users prior to their diagnosis. They typically started using it for MS symptom relief 2-3 years after receiving their diagnosis. By the time they were approached for study participation, they had been using cannabis four to five times per day or more for an average of 7 years for relief of symptoms, including incontinence, spasticity, poor sleep, headaches, and difficulties in eating.

All participants were willing to try 28 days of abstinence; half were randomized to do so, while the others stayed the course. Study endpoints included change from baseline to day 28 in the Brief Repeatable Neuropsychological Battery, functional MRI done while taking the Symbol Digit Modalities Test, and urine testing to assure compliance with abstinence.

By day 28, the abstinence group – and with one exception, urine testing confirmed they were bona fide cannabis quitters for the study duration – performed significantly better on the neuropsychological test battery than at baseline, with an associated significant increase in brain activation in the bilateral inferior frontal gyri, as well as the caudate and declive cerebellum while executing the Symbol Digit Modalities Test. The control group who kept on using cannabis showed no such improvements.

The full study details were published in conjunction with Ms. Meza’s presentation (Brain. 2019 Sep 1;142[9]:2800-12).

She reported having no financial conflicts regarding the study, funded by the Multiple Sclerosis Society of Canada.

[email protected]

SOURCE: Meza C. ECTRIMS 2019, Abstract P542.

I recently encountered an article aimed at parents who were struggling with what to do about their child’s persistent attachment to his pacifier (“How to Ditch the Pacifier,” by Anna Nowogrodski, New York Times, 2019 Sept. 16). For the most part, the author presented a sampling of sound advice from pediatricians and other health experts.

Travis Manley/Thinkstock

Most children will abandon their pacifiers at a time that is consistent with their developmental stage. Pacifiers seldom do any permanent damage, although they aren’t terribly appealing to look at when hanging out of a toddling toddler’s mouth. Parents were urged to be patient and consistent and were told that allowing the gooey thing to self-destruct often works, as does accelerating the process with a razor blade. Enlisting the aid of the Pacifier Fairy was suggested, but I’m not so sure that would work terribly well.

As I finished perusing the article, I couldn’t help think of how this vexing issue of pacifier removal can be avoided if parents follow a simple rule when they first introduced a pacifier to their child. If experienced parents think back to when they first resorted to using the pacifier, it wasn’t because the plastic and rubber gadget was a family heirloom that had been passed down from generation to generation like an engraved silver spoon. It wasn’t because the dentist told them that children who use pacifiers are less likely to need braces on their teeth. Nor was it a rumor filtered down from speech therapists that pacifiers improve articulation.

Parents reach for a pacifier in hopes that it will help their child will fall asleep. I think most parents of older children agree that at the beginning the pacifier was first and foremost a sleep aid. But here is where the critical oversight occurs: If you give your children pacifiers when you want them to go to sleep, why not simply add the stipulation of where you would like them to go to sleep as well?

Most parents prefer that their children sleep in their own space. We can argue of whether that should be in a side sleeper or their own crib, but most parents don’t want their 3-year-olds sleeping in their bed. Nor do they want their children sleeping on the couch in the living room with them while they watch a movie at 10:30 at night. And as pediatricians, we prefer that children not sleep with their necks flexed in a car seat or baby rocker, particularly if they’re a preemie.

So why not adopt the simple family rule that the child can use a pacifier whenever it seems needed, but only in bed? Augmenting the primary association between sleep and the pacifier by adding a place has several important advantages. It gives parents more control of where their children will sleep or, more importantly, where they won’t be sleeping. It helps transitions to nonhome sleeping places like day care and long trips to grandma’s house go more smoothly.

Even more importantly, the crib/pacifier association helps parents who have had trouble reading their children’s cues. If they want a pacifier, it means they are tired and want to go to where the pacifier lives: bed

Finally, maintaining the link between sleeping and the pacifier promotes a more natural weaning process than going cold turkey or hiring the Pacifier Fairy. As naps disappear, the pacifier gradually become a less obvious accessory in the child’s life. However, it may linger in the background as a reminder of when the child needs some restorative sleep.

Of course, helping parents to think clearly enough to create and enforce a simple rule long enough to forge a healthy association when they are sleep deprived themselves is just another one of those challenges we must accept as concerned primary care pediatricians.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “Is My Child Overtired? The Sleep Solution for Raising Happier, Healthier Children.” Email him at [email protected].

I recently encountered an article aimed at parents who were struggling with what to do about their child’s persistent attachment to his pacifier (“How to Ditch the Pacifier,” by Anna Nowogrodski, New York Times, 2019 Sept. 16). For the most part, the author presented a sampling of sound advice from pediatricians and other health experts.

Travis Manley/Thinkstock

Most children will abandon their pacifiers at a time that is consistent with their developmental stage. Pacifiers seldom do any permanent damage, although they aren’t terribly appealing to look at when hanging out of a toddling toddler’s mouth. Parents were urged to be patient and consistent and were told that allowing the gooey thing to self-destruct often works, as does accelerating the process with a razor blade. Enlisting the aid of the Pacifier Fairy was suggested, but I’m not so sure that would work terribly well.

As I finished perusing the article, I couldn’t help think of how this vexing issue of pacifier removal can be avoided if parents follow a simple rule when they first introduced a pacifier to their child. If experienced parents think back to when they first resorted to using the pacifier, it wasn’t because the plastic and rubber gadget was a family heirloom that had been passed down from generation to generation like an engraved silver spoon. It wasn’t because the dentist told them that children who use pacifiers are less likely to need braces on their teeth. Nor was it a rumor filtered down from speech therapists that pacifiers improve articulation.

Parents reach for a pacifier in hopes that it will help their child will fall asleep. I think most parents of older children agree that at the beginning the pacifier was first and foremost a sleep aid. But here is where the critical oversight occurs: If you give your children pacifiers when you want them to go to sleep, why not simply add the stipulation of where you would like them to go to sleep as well?

Most parents prefer that their children sleep in their own space. We can argue of whether that should be in a side sleeper or their own crib, but most parents don’t want their 3-year-olds sleeping in their bed. Nor do they want their children sleeping on the couch in the living room with them while they watch a movie at 10:30 at night. And as pediatricians, we prefer that children not sleep with their necks flexed in a car seat or baby rocker, particularly if they’re a preemie.

So why not adopt the simple family rule that the child can use a pacifier whenever it seems needed, but only in bed? Augmenting the primary association between sleep and the pacifier by adding a place has several important advantages. It gives parents more control of where their children will sleep or, more importantly, where they won’t be sleeping. It helps transitions to nonhome sleeping places like day care and long trips to grandma’s house go more smoothly.

Even more importantly, the crib/pacifier association helps parents who have had trouble reading their children’s cues. If they want a pacifier, it means they are tired and want to go to where the pacifier lives: bed

Finally, maintaining the link between sleeping and the pacifier promotes a more natural weaning process than going cold turkey or hiring the Pacifier Fairy. As naps disappear, the pacifier gradually become a less obvious accessory in the child’s life. However, it may linger in the background as a reminder of when the child needs some restorative sleep.

Of course, helping parents to think clearly enough to create and enforce a simple rule long enough to forge a healthy association when they are sleep deprived themselves is just another one of those challenges we must accept as concerned primary care pediatricians.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “Is My Child Overtired? The Sleep Solution for Raising Happier, Healthier Children.” Email him at [email protected].

I recently encountered an article aimed at parents who were struggling with what to do about their child’s persistent attachment to his pacifier (“How to Ditch the Pacifier,” by Anna Nowogrodski, New York Times, 2019 Sept. 16). For the most part, the author presented a sampling of sound advice from pediatricians and other health experts.

Travis Manley/Thinkstock

Most children will abandon their pacifiers at a time that is consistent with their developmental stage. Pacifiers seldom do any permanent damage, although they aren’t terribly appealing to look at when hanging out of a toddling toddler’s mouth. Parents were urged to be patient and consistent and were told that allowing the gooey thing to self-destruct often works, as does accelerating the process with a razor blade. Enlisting the aid of the Pacifier Fairy was suggested, but I’m not so sure that would work terribly well.

As I finished perusing the article, I couldn’t help think of how this vexing issue of pacifier removal can be avoided if parents follow a simple rule when they first introduced a pacifier to their child. If experienced parents think back to when they first resorted to using the pacifier, it wasn’t because the plastic and rubber gadget was a family heirloom that had been passed down from generation to generation like an engraved silver spoon. It wasn’t because the dentist told them that children who use pacifiers are less likely to need braces on their teeth. Nor was it a rumor filtered down from speech therapists that pacifiers improve articulation.

Parents reach for a pacifier in hopes that it will help their child will fall asleep. I think most parents of older children agree that at the beginning the pacifier was first and foremost a sleep aid. But here is where the critical oversight occurs: If you give your children pacifiers when you want them to go to sleep, why not simply add the stipulation of where you would like them to go to sleep as well?

Most parents prefer that their children sleep in their own space. We can argue of whether that should be in a side sleeper or their own crib, but most parents don’t want their 3-year-olds sleeping in their bed. Nor do they want their children sleeping on the couch in the living room with them while they watch a movie at 10:30 at night. And as pediatricians, we prefer that children not sleep with their necks flexed in a car seat or baby rocker, particularly if they’re a preemie.

So why not adopt the simple family rule that the child can use a pacifier whenever it seems needed, but only in bed? Augmenting the primary association between sleep and the pacifier by adding a place has several important advantages. It gives parents more control of where their children will sleep or, more importantly, where they won’t be sleeping. It helps transitions to nonhome sleeping places like day care and long trips to grandma’s house go more smoothly.

Even more importantly, the crib/pacifier association helps parents who have had trouble reading their children’s cues. If they want a pacifier, it means they are tired and want to go to where the pacifier lives: bed

Finally, maintaining the link between sleeping and the pacifier promotes a more natural weaning process than going cold turkey or hiring the Pacifier Fairy. As naps disappear, the pacifier gradually become a less obvious accessory in the child’s life. However, it may linger in the background as a reminder of when the child needs some restorative sleep.

Of course, helping parents to think clearly enough to create and enforce a simple rule long enough to forge a healthy association when they are sleep deprived themselves is just another one of those challenges we must accept as concerned primary care pediatricians.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “Is My Child Overtired? The Sleep Solution for Raising Happier, Healthier Children.” Email him at [email protected].

The Food and Drug Administration approved rituximab (Rituxan) by injection to treat granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) in children 2 years of age and older in combination with glucocorticoid treatment, according to an FDA news release.

Olivier Le Moal/Getty Images

These rare forms of vasculitis damage small blood vessels through inflammation and can lead to serious organ failure, including lungs and kidneys.

The Genentech drug received priority review and an orphan drug designation based on the results of a pediatric clinical trial of 25 patients aged 6-17 years with active GPA or MPA who were treated with rituximab in an international multicenter, open-label, uncontrolled study. Patients in the trial were also given methylprednisolone prior to starting treatment.

The trial consisted of a 6-month remission induction phase where patients were treated only with rituximab and glucocorticoids. In addition, patients who had not achieved remission could receive additional treatment, including other therapies, at the discretion of the investigator, according to the FDA. By 6 months, 14 of the patients were in remission, and after 18 months, all 25 patients were in remission.

Rituximab contains a boxed warning regarding increased risks of fatal infusion reactions, potentially fatal severe skin and mouth reactions, hepatitis B virus reactivation that may cause serious or lethal liver problems, and progressive multifocal leukoencephalopathy, a rare, potentially lethal brain infection.

The trial was conducted and sponsored by F. Hoffmann-La Roche, which owns Genentech.

[email protected]

The Food and Drug Administration approved rituximab (Rituxan) by injection to treat granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) in children 2 years of age and older in combination with glucocorticoid treatment, according to an FDA news release.

Olivier Le Moal/Getty Images

These rare forms of vasculitis damage small blood vessels through inflammation and can lead to serious organ failure, including lungs and kidneys.

The Genentech drug received priority review and an orphan drug designation based on the results of a pediatric clinical trial of 25 patients aged 6-17 years with active GPA or MPA who were treated with rituximab in an international multicenter, open-label, uncontrolled study. Patients in the trial were also given methylprednisolone prior to starting treatment.

The trial consisted of a 6-month remission induction phase where patients were treated only with rituximab and glucocorticoids. In addition, patients who had not achieved remission could receive additional treatment, including other therapies, at the discretion of the investigator, according to the FDA. By 6 months, 14 of the patients were in remission, and after 18 months, all 25 patients were in remission.

Rituximab contains a boxed warning regarding increased risks of fatal infusion reactions, potentially fatal severe skin and mouth reactions, hepatitis B virus reactivation that may cause serious or lethal liver problems, and progressive multifocal leukoencephalopathy, a rare, potentially lethal brain infection.

The trial was conducted and sponsored by F. Hoffmann-La Roche, which owns Genentech.

[email protected]

The Food and Drug Administration approved rituximab (Rituxan) by injection to treat granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) in children 2 years of age and older in combination with glucocorticoid treatment, according to an FDA news release.

Olivier Le Moal/Getty Images

These rare forms of vasculitis damage small blood vessels through inflammation and can lead to serious organ failure, including lungs and kidneys.

The Genentech drug received priority review and an orphan drug designation based on the results of a pediatric clinical trial of 25 patients aged 6-17 years with active GPA or MPA who were treated with rituximab in an international multicenter, open-label, uncontrolled study. Patients in the trial were also given methylprednisolone prior to starting treatment.

The trial consisted of a 6-month remission induction phase where patients were treated only with rituximab and glucocorticoids. In addition, patients who had not achieved remission could receive additional treatment, including other therapies, at the discretion of the investigator, according to the FDA. By 6 months, 14 of the patients were in remission, and after 18 months, all 25 patients were in remission.

Rituximab contains a boxed warning regarding increased risks of fatal infusion reactions, potentially fatal severe skin and mouth reactions, hepatitis B virus reactivation that may cause serious or lethal liver problems, and progressive multifocal leukoencephalopathy, a rare, potentially lethal brain infection.

The trial was conducted and sponsored by F. Hoffmann-La Roche, which owns Genentech.

[email protected]

Question: Which one of the following statements regarding medication warnings is incorrect?

A. The drug package “insert” or “label” contains, among other things, a drug’s pharmacology, indications, contraindications, risks and warnings.

B. The Physicians’ Desk Reference (PDR) is an annually updated drug compendium, which can be admitted into evidence as a learned treatise.

C. Drug labeling is a dual responsibility of the manufacturer and the Food and Drug Administration.

D. The FDA is solely responsible for a drug’s warnings and sets the absolute standard of care regarding side effects and complications.

E. State law can impose liability for negligent failure to warn even if the FDA has not included the warning in the drug’s label.

Answer: D. Should a prescription drug or medical device lead to harm, an injured party can sue the manufacturer who had placed it into the stream of commerce. In medical products liability, injured plaintiffs frequently claim a failure to warn of known risks. An example is the cardiovascular deaths caused by Vioxx, a nonsteroidal, anti-inflammatory drug that was withdrawn in 2004. Other examples alleging failure to warn are Actos-associated bladder cancer and Baycol-related rhabdomyolysis. At the time of product approval, the FDA sets out the labeling that goes with each drug, and then makes periodic changes to reflect new indications, warnings and risks. The manufacturer has the prime responsibility for submitting all updated information, especially of augmented risks that come with field experience. In 2012, for example, the FDA mandated the revision of the labeling of Lipitor and other statins to warn of the increased risk of diabetes.

The drug manufacturer stands in the unique position as having the most detailed and up-to-date data and bears a serious responsibility to submit its full findings to the FDA, including its request for label change. Litigation over failure to warn of risks frequently turns on whether the drug manufacturer knew or should have known, had failed to inform the FDA, or whether the FDA itself had declined to make the changes, e.g., because of incomplete or premature data. Notwithstanding the FDA’s overarching federal status, a plaintiff may still attempt to use state tort law to hold a manufacturer liable should the federally approved labeling be silent on the matter.

Two U.S. Supreme Court cases sought to clarify the rules under which a drug manufacturer, when sued for failure to warn, may seek protection under its FDA-approved labeling. The first case involved Diana Levine, a Vermont musician and migraine sufferer, who lost her arm after the drug Phenergan, given by intravenous push, accidentally entered an artery and caused gangrene. Although the intravenous use of Phenergan is approved by the FDA and the risk of such use is clearly stated in the drug’s package insert, the lawsuit alleged that under state law, such a warning was inadequate and should have been strengthened to prohibit this mode of administration. A Vermont jury awarded damages of $6.7 million. On appeal, Wyeth, the defendant pharmaceutical company, maintained that its warning was appropriate, as it had been approved by the federal government through the FDA. It further argued that the drug’s package insert could not be unilaterally altered or modified without running afoul of federal regulations.

In a 6-3 decision,¹ the U.S. Supreme Court ruled that the manufacturer was in fact at liberty to issue a more stringent warning, and FDA approval does not bar lawsuits. The Court opined that “Federal law does not pre-empt Levine’s claim that Phenergan’s label did not contain an adequate warning about the IV-push method of administration.” Wyeth had argued that it was impossible for the company to provide additional warnings, since it was the FDA that made the sole determination of the nature and scope of a drug’s label. However, the court held that Wyeth never attempted to change the label to warn of the risk and failed to provide “clear” evidence that the FDA would have prevented it from changing its label. Without defining what constituted “clear” evidence, it rejected Wyeth’s broad assertion that unilaterally changing the Phenergan label would have violated federal law, which was based on the fundamental misunderstanding that the FDA, rather than the manufacturer, bears primary responsibility for drug labeling.

In 2019, the landmark case of Merck Sharp & Dohme Corp v. Albrecht et al.² reached the U.S. Supreme Court. This class-action suit involved more than 500 individuals who took Fosamax, an effective anti-resorptive drug for treating osteoporosis, and suffered atypical femoral fractures between 1999 and 2010. When the FDA first approved of the manufacture and sale of Fosamax in 1995, the Fosamax label did not warn of the then-speculative risk of atypical femoral fractures. But stronger evidence connecting Fosamax to atypical fractures developed after 1995, prompting the FDA to add a warning in 2011. Merck argued that plaintiffs’ state-law failure-to-warn claims should be dismissed as preempted by federal law. It conceded that the FDA regulations would have permitted Merck to try to change the label to add a warning before 2010 but believed the FDA would have rejected that attempt. In particular, it claimed that the FDA’s rejection of Merck’s 2008 attempt to warn of a risk of “stress fractures” showed that the FDA would also have rejected any attempt by Merck to warn of the risk of atypical femoral fractures. In short, Merck was relying on the legal doctrine of “impossibility preemption,” i.e., it was impossible to comply with both state law (adequate label warning of atypical fractures) and federal law (FDA control of warning labels). The plaintiffs’ position was that Merck’s proposed warning to the FDA had minimized the seriousness of the femoral fracture risk, characterizing them only as “stress fractures.”³

The Court’s earlier Levine decision had held that a state-law failure-to-warn claim is preempted where there is “clear” evidence the FDA would not have approved a label change. In the Albrecht decision, which also sided with the plaintiffs, the court indicated that “Clear evidence is evidence that shows the court that the drug manufacturer fully informed the FDA of the justifications for the warning required by state law and that the FDA, in turn, informed the drug manufacturer that the FDA would not approve a change to the drug’s label to include that warning.” The court also held that issues relating to presumption of impossibility are law-based, and thus it remains for the judge, not the jury, to make that determination.

Issuing timely warnings regarding medical products promotes patient safety, and the law appears to place the major onus on the manufacturer. Still, striking the proper balance is important. During oral arguments in Albrecht, Associate Justice Neil Gorsuch is said to have cautioned against “ ... incentives for companies to submit weakly supported label changes to the agency, knowing that when those label changes are rejected the companies will be free of further liability.” And as pointed out in the earlier cited Johnston article: “ ... a system that creates incentives for manufacturers to over-warn physicians and patients could harm patients by listing the important warnings of adverse effects among numerous less important warnings, which may discourage physicians and patients from choosing potentially useful drugs. On the other hand, a shift of responsibility for labeling to the FDA raises questions about whether the agency, which has resources that are dwarfed by the combined resources of industry, is necessarily capable to serve in this role ...”

Finally, this issue is more complex for devices because of the Medical Device Amendments Act of 1976 (MDA), which may preempt state-based lawsuits. In a claim brought after a Medtronic catheter ruptured in a patient’s coronary artery during heart surgery, the plaintiff alleged that the device was designed, labeled, and manufactured in a manner that violated New York common law. The case was appealed to the U.S. Supreme Court. The court held that the MDA preempted petitioner’s common-law claims challenging the safety or effectiveness of a medical device marketed in a form that received premarket approval from the FDA.⁴ The court ruled that MDA created a scheme of federal safety oversight for medical devices while sweeping back state oversight schemes.
 

Dr. Tan is professor emeritus of medicine and former adjunct professor of law at the University of Hawaii. This article is meant to be educational and does not constitute medical, ethical, or legal advice. For additional information, readers may contact the author at [email protected].

References

1. Wyeth v. Levine, 555 U.S. 2 (2009).

2. Merck, Sharp & Dohme Corp. v. Albrecht et al., 587 U. S. ____ (2019).

3. Johnston MC et al., A new Supreme Court ruling on drug liability. JAMA 2019;322(7):607-8.

4. Riegel v. Medtronic, 128 S. Ct. 999 (2008).

Question: Which one of the following statements regarding medication warnings is incorrect?

A. The drug package “insert” or “label” contains, among other things, a drug’s pharmacology, indications, contraindications, risks and warnings.

B. The Physicians’ Desk Reference (PDR) is an annually updated drug compendium, which can be admitted into evidence as a learned treatise.

C. Drug labeling is a dual responsibility of the manufacturer and the Food and Drug Administration.

D. The FDA is solely responsible for a drug’s warnings and sets the absolute standard of care regarding side effects and complications.

E. State law can impose liability for negligent failure to warn even if the FDA has not included the warning in the drug’s label.

Answer: D. Should a prescription drug or medical device lead to harm, an injured party can sue the manufacturer who had placed it into the stream of commerce. In medical products liability, injured plaintiffs frequently claim a failure to warn of known risks. An example is the cardiovascular deaths caused by Vioxx, a nonsteroidal, anti-inflammatory drug that was withdrawn in 2004. Other examples alleging failure to warn are Actos-associated bladder cancer and Baycol-related rhabdomyolysis. At the time of product approval, the FDA sets out the labeling that goes with each drug, and then makes periodic changes to reflect new indications, warnings and risks. The manufacturer has the prime responsibility for submitting all updated information, especially of augmented risks that come with field experience. In 2012, for example, the FDA mandated the revision of the labeling of Lipitor and other statins to warn of the increased risk of diabetes.

The drug manufacturer stands in the unique position as having the most detailed and up-to-date data and bears a serious responsibility to submit its full findings to the FDA, including its request for label change. Litigation over failure to warn of risks frequently turns on whether the drug manufacturer knew or should have known, had failed to inform the FDA, or whether the FDA itself had declined to make the changes, e.g., because of incomplete or premature data. Notwithstanding the FDA’s overarching federal status, a plaintiff may still attempt to use state tort law to hold a manufacturer liable should the federally approved labeling be silent on the matter.

Two U.S. Supreme Court cases sought to clarify the rules under which a drug manufacturer, when sued for failure to warn, may seek protection under its FDA-approved labeling. The first case involved Diana Levine, a Vermont musician and migraine sufferer, who lost her arm after the drug Phenergan, given by intravenous push, accidentally entered an artery and caused gangrene. Although the intravenous use of Phenergan is approved by the FDA and the risk of such use is clearly stated in the drug’s package insert, the lawsuit alleged that under state law, such a warning was inadequate and should have been strengthened to prohibit this mode of administration. A Vermont jury awarded damages of $6.7 million. On appeal, Wyeth, the defendant pharmaceutical company, maintained that its warning was appropriate, as it had been approved by the federal government through the FDA. It further argued that the drug’s package insert could not be unilaterally altered or modified without running afoul of federal regulations.

In a 6-3 decision,¹ the U.S. Supreme Court ruled that the manufacturer was in fact at liberty to issue a more stringent warning, and FDA approval does not bar lawsuits. The Court opined that “Federal law does not pre-empt Levine’s claim that Phenergan’s label did not contain an adequate warning about the IV-push method of administration.” Wyeth had argued that it was impossible for the company to provide additional warnings, since it was the FDA that made the sole determination of the nature and scope of a drug’s label. However, the court held that Wyeth never attempted to change the label to warn of the risk and failed to provide “clear” evidence that the FDA would have prevented it from changing its label. Without defining what constituted “clear” evidence, it rejected Wyeth’s broad assertion that unilaterally changing the Phenergan label would have violated federal law, which was based on the fundamental misunderstanding that the FDA, rather than the manufacturer, bears primary responsibility for drug labeling.

In 2019, the landmark case of Merck Sharp & Dohme Corp v. Albrecht et al.² reached the U.S. Supreme Court. This class-action suit involved more than 500 individuals who took Fosamax, an effective anti-resorptive drug for treating osteoporosis, and suffered atypical femoral fractures between 1999 and 2010. When the FDA first approved of the manufacture and sale of Fosamax in 1995, the Fosamax label did not warn of the then-speculative risk of atypical femoral fractures. But stronger evidence connecting Fosamax to atypical fractures developed after 1995, prompting the FDA to add a warning in 2011. Merck argued that plaintiffs’ state-law failure-to-warn claims should be dismissed as preempted by federal law. It conceded that the FDA regulations would have permitted Merck to try to change the label to add a warning before 2010 but believed the FDA would have rejected that attempt. In particular, it claimed that the FDA’s rejection of Merck’s 2008 attempt to warn of a risk of “stress fractures” showed that the FDA would also have rejected any attempt by Merck to warn of the risk of atypical femoral fractures. In short, Merck was relying on the legal doctrine of “impossibility preemption,” i.e., it was impossible to comply with both state law (adequate label warning of atypical fractures) and federal law (FDA control of warning labels). The plaintiffs’ position was that Merck’s proposed warning to the FDA had minimized the seriousness of the femoral fracture risk, characterizing them only as “stress fractures.”³

The Court’s earlier Levine decision had held that a state-law failure-to-warn claim is preempted where there is “clear” evidence the FDA would not have approved a label change. In the Albrecht decision, which also sided with the plaintiffs, the court indicated that “Clear evidence is evidence that shows the court that the drug manufacturer fully informed the FDA of the justifications for the warning required by state law and that the FDA, in turn, informed the drug manufacturer that the FDA would not approve a change to the drug’s label to include that warning.” The court also held that issues relating to presumption of impossibility are law-based, and thus it remains for the judge, not the jury, to make that determination.

Issuing timely warnings regarding medical products promotes patient safety, and the law appears to place the major onus on the manufacturer. Still, striking the proper balance is important. During oral arguments in Albrecht, Associate Justice Neil Gorsuch is said to have cautioned against “ ... incentives for companies to submit weakly supported label changes to the agency, knowing that when those label changes are rejected the companies will be free of further liability.” And as pointed out in the earlier cited Johnston article: “ ... a system that creates incentives for manufacturers to over-warn physicians and patients could harm patients by listing the important warnings of adverse effects among numerous less important warnings, which may discourage physicians and patients from choosing potentially useful drugs. On the other hand, a shift of responsibility for labeling to the FDA raises questions about whether the agency, which has resources that are dwarfed by the combined resources of industry, is necessarily capable to serve in this role ...”

Finally, this issue is more complex for devices because of the Medical Device Amendments Act of 1976 (MDA), which may preempt state-based lawsuits. In a claim brought after a Medtronic catheter ruptured in a patient’s coronary artery during heart surgery, the plaintiff alleged that the device was designed, labeled, and manufactured in a manner that violated New York common law. The case was appealed to the U.S. Supreme Court. The court held that the MDA preempted petitioner’s common-law claims challenging the safety or effectiveness of a medical device marketed in a form that received premarket approval from the FDA.⁴ The court ruled that MDA created a scheme of federal safety oversight for medical devices while sweeping back state oversight schemes.
 

Dr. Tan is professor emeritus of medicine and former adjunct professor of law at the University of Hawaii. This article is meant to be educational and does not constitute medical, ethical, or legal advice. For additional information, readers may contact the author at [email protected].

References

1. Wyeth v. Levine, 555 U.S. 2 (2009).

2. Merck, Sharp & Dohme Corp. v. Albrecht et al., 587 U. S. ____ (2019).

3. Johnston MC et al., A new Supreme Court ruling on drug liability. JAMA 2019;322(7):607-8.

4. Riegel v. Medtronic, 128 S. Ct. 999 (2008).

Question: Which one of the following statements regarding medication warnings is incorrect?

A. The drug package “insert” or “label” contains, among other things, a drug’s pharmacology, indications, contraindications, risks and warnings.

B. The Physicians’ Desk Reference (PDR) is an annually updated drug compendium, which can be admitted into evidence as a learned treatise.

C. Drug labeling is a dual responsibility of the manufacturer and the Food and Drug Administration.

D. The FDA is solely responsible for a drug’s warnings and sets the absolute standard of care regarding side effects and complications.

E. State law can impose liability for negligent failure to warn even if the FDA has not included the warning in the drug’s label.

Answer: D. Should a prescription drug or medical device lead to harm, an injured party can sue the manufacturer who had placed it into the stream of commerce. In medical products liability, injured plaintiffs frequently claim a failure to warn of known risks. An example is the cardiovascular deaths caused by Vioxx, a nonsteroidal, anti-inflammatory drug that was withdrawn in 2004. Other examples alleging failure to warn are Actos-associated bladder cancer and Baycol-related rhabdomyolysis. At the time of product approval, the FDA sets out the labeling that goes with each drug, and then makes periodic changes to reflect new indications, warnings and risks. The manufacturer has the prime responsibility for submitting all updated information, especially of augmented risks that come with field experience. In 2012, for example, the FDA mandated the revision of the labeling of Lipitor and other statins to warn of the increased risk of diabetes.

The drug manufacturer stands in the unique position as having the most detailed and up-to-date data and bears a serious responsibility to submit its full findings to the FDA, including its request for label change. Litigation over failure to warn of risks frequently turns on whether the drug manufacturer knew or should have known, had failed to inform the FDA, or whether the FDA itself had declined to make the changes, e.g., because of incomplete or premature data. Notwithstanding the FDA’s overarching federal status, a plaintiff may still attempt to use state tort law to hold a manufacturer liable should the federally approved labeling be silent on the matter.

Two U.S. Supreme Court cases sought to clarify the rules under which a drug manufacturer, when sued for failure to warn, may seek protection under its FDA-approved labeling. The first case involved Diana Levine, a Vermont musician and migraine sufferer, who lost her arm after the drug Phenergan, given by intravenous push, accidentally entered an artery and caused gangrene. Although the intravenous use of Phenergan is approved by the FDA and the risk of such use is clearly stated in the drug’s package insert, the lawsuit alleged that under state law, such a warning was inadequate and should have been strengthened to prohibit this mode of administration. A Vermont jury awarded damages of $6.7 million. On appeal, Wyeth, the defendant pharmaceutical company, maintained that its warning was appropriate, as it had been approved by the federal government through the FDA. It further argued that the drug’s package insert could not be unilaterally altered or modified without running afoul of federal regulations.

In a 6-3 decision,¹ the U.S. Supreme Court ruled that the manufacturer was in fact at liberty to issue a more stringent warning, and FDA approval does not bar lawsuits. The Court opined that “Federal law does not pre-empt Levine’s claim that Phenergan’s label did not contain an adequate warning about the IV-push method of administration.” Wyeth had argued that it was impossible for the company to provide additional warnings, since it was the FDA that made the sole determination of the nature and scope of a drug’s label. However, the court held that Wyeth never attempted to change the label to warn of the risk and failed to provide “clear” evidence that the FDA would have prevented it from changing its label. Without defining what constituted “clear” evidence, it rejected Wyeth’s broad assertion that unilaterally changing the Phenergan label would have violated federal law, which was based on the fundamental misunderstanding that the FDA, rather than the manufacturer, bears primary responsibility for drug labeling.

In 2019, the landmark case of Merck Sharp & Dohme Corp v. Albrecht et al.² reached the U.S. Supreme Court. This class-action suit involved more than 500 individuals who took Fosamax, an effective anti-resorptive drug for treating osteoporosis, and suffered atypical femoral fractures between 1999 and 2010. When the FDA first approved of the manufacture and sale of Fosamax in 1995, the Fosamax label did not warn of the then-speculative risk of atypical femoral fractures. But stronger evidence connecting Fosamax to atypical fractures developed after 1995, prompting the FDA to add a warning in 2011. Merck argued that plaintiffs’ state-law failure-to-warn claims should be dismissed as preempted by federal law. It conceded that the FDA regulations would have permitted Merck to try to change the label to add a warning before 2010 but believed the FDA would have rejected that attempt. In particular, it claimed that the FDA’s rejection of Merck’s 2008 attempt to warn of a risk of “stress fractures” showed that the FDA would also have rejected any attempt by Merck to warn of the risk of atypical femoral fractures. In short, Merck was relying on the legal doctrine of “impossibility preemption,” i.e., it was impossible to comply with both state law (adequate label warning of atypical fractures) and federal law (FDA control of warning labels). The plaintiffs’ position was that Merck’s proposed warning to the FDA had minimized the seriousness of the femoral fracture risk, characterizing them only as “stress fractures.”³

The Court’s earlier Levine decision had held that a state-law failure-to-warn claim is preempted where there is “clear” evidence the FDA would not have approved a label change. In the Albrecht decision, which also sided with the plaintiffs, the court indicated that “Clear evidence is evidence that shows the court that the drug manufacturer fully informed the FDA of the justifications for the warning required by state law and that the FDA, in turn, informed the drug manufacturer that the FDA would not approve a change to the drug’s label to include that warning.” The court also held that issues relating to presumption of impossibility are law-based, and thus it remains for the judge, not the jury, to make that determination.

Issuing timely warnings regarding medical products promotes patient safety, and the law appears to place the major onus on the manufacturer. Still, striking the proper balance is important. During oral arguments in Albrecht, Associate Justice Neil Gorsuch is said to have cautioned against “ ... incentives for companies to submit weakly supported label changes to the agency, knowing that when those label changes are rejected the companies will be free of further liability.” And as pointed out in the earlier cited Johnston article: “ ... a system that creates incentives for manufacturers to over-warn physicians and patients could harm patients by listing the important warnings of adverse effects among numerous less important warnings, which may discourage physicians and patients from choosing potentially useful drugs. On the other hand, a shift of responsibility for labeling to the FDA raises questions about whether the agency, which has resources that are dwarfed by the combined resources of industry, is necessarily capable to serve in this role ...”

Finally, this issue is more complex for devices because of the Medical Device Amendments Act of 1976 (MDA), which may preempt state-based lawsuits. In a claim brought after a Medtronic catheter ruptured in a patient’s coronary artery during heart surgery, the plaintiff alleged that the device was designed, labeled, and manufactured in a manner that violated New York common law. The case was appealed to the U.S. Supreme Court. The court held that the MDA preempted petitioner’s common-law claims challenging the safety or effectiveness of a medical device marketed in a form that received premarket approval from the FDA.⁴ The court ruled that MDA created a scheme of federal safety oversight for medical devices while sweeping back state oversight schemes.
 

Dr. Tan is professor emeritus of medicine and former adjunct professor of law at the University of Hawaii. This article is meant to be educational and does not constitute medical, ethical, or legal advice. For additional information, readers may contact the author at [email protected].

References

1. Wyeth v. Levine, 555 U.S. 2 (2009).

2. Merck, Sharp & Dohme Corp. v. Albrecht et al., 587 U. S. ____ (2019).

3. Johnston MC et al., A new Supreme Court ruling on drug liability. JAMA 2019;322(7):607-8.

4. Riegel v. Medtronic, 128 S. Ct. 999 (2008).

If you are a young vascular surgeon from outside North America, consider applying for the International Scholars Program. Recipients of the award will receive a $5,000 stipend, spend two weeks in the U.S, visiting universities and clinics, and attend the 2020 VAM in Toronto. Scholars will work with a mentor to schedule various vascular program visits, including clinical, teaching and research programs. Apply before Oct. 7 to be considered. Learn more here.

If you are a young vascular surgeon from outside North America, consider applying for the International Scholars Program. Recipients of the award will receive a $5,000 stipend, spend two weeks in the U.S, visiting universities and clinics, and attend the 2020 VAM in Toronto. Scholars will work with a mentor to schedule various vascular program visits, including clinical, teaching and research programs. Apply before Oct. 7 to be considered. Learn more here.

If you are a young vascular surgeon from outside North America, consider applying for the International Scholars Program. Recipients of the award will receive a $5,000 stipend, spend two weeks in the U.S, visiting universities and clinics, and attend the 2020 VAM in Toronto. Scholars will work with a mentor to schedule various vascular program visits, including clinical, teaching and research programs. Apply before Oct. 7 to be considered. Learn more here.

The Food and Drug Administration has approved canagliflozin (Invokana) for the treatment of diabetic kidney disease and for reduction of the risk of hospitalization for heart failure in patients with type 2 diabetes and diabetic kidney disease, which makes it the first drug indicated for diabetic kidney disease treatment in 20 years.

FDA approval, which was announced in a press release by Janssen, the drug’s manufacturer, is based on results from the phase 3 CREDENCE trial. In that study patients with type 2 diabetes and chronic diabetic kidney disease received either 100 mg canagliflozin or placebo. Patients who received canagliflozin experienced a 30% reduction in the risk of the primary composite endpoint, which included end-stage kidney disease, doubling of serum creatinine, and renal or cardiovascular death. The risk of secondary outcomes were also reduced in patients receiving canagliflozin, including a 39% reduction in the risk of hospitalization for heart failure.

The most common adverse events associated with canagliflozin, according to the label, are female genital mycotic infections, urinary tract infection, and increased urination. Serious adverse events associated with canagliflozin include ketoacidosis, kidney problems, serious urinary tract infections, hypoglycemia, necrotizing fasciitis, serious allergic reaction, and bone fractures.

“The real battle to turn the tide on kidney disease is in early detection and slowing its progression so that patients stay healthier and fewer patients reach kidney failure,” LaVerne A. Burton, president and CEO of the American Kidney Fund, said in the press release. “We are so grateful that advances in kidney disease research are producing treatment options that help to slow the progression of diabetic kidney disease and reduce the risk of hospitalization for heart failure.”

Find the full press release on the Janssen website.

[email protected]

The Food and Drug Administration has approved canagliflozin (Invokana) for the treatment of diabetic kidney disease and for reduction of the risk of hospitalization for heart failure in patients with type 2 diabetes and diabetic kidney disease, which makes it the first drug indicated for diabetic kidney disease treatment in 20 years.

FDA approval, which was announced in a press release by Janssen, the drug’s manufacturer, is based on results from the phase 3 CREDENCE trial. In that study patients with type 2 diabetes and chronic diabetic kidney disease received either 100 mg canagliflozin or placebo. Patients who received canagliflozin experienced a 30% reduction in the risk of the primary composite endpoint, which included end-stage kidney disease, doubling of serum creatinine, and renal or cardiovascular death. The risk of secondary outcomes were also reduced in patients receiving canagliflozin, including a 39% reduction in the risk of hospitalization for heart failure.

The most common adverse events associated with canagliflozin, according to the label, are female genital mycotic infections, urinary tract infection, and increased urination. Serious adverse events associated with canagliflozin include ketoacidosis, kidney problems, serious urinary tract infections, hypoglycemia, necrotizing fasciitis, serious allergic reaction, and bone fractures.

“The real battle to turn the tide on kidney disease is in early detection and slowing its progression so that patients stay healthier and fewer patients reach kidney failure,” LaVerne A. Burton, president and CEO of the American Kidney Fund, said in the press release. “We are so grateful that advances in kidney disease research are producing treatment options that help to slow the progression of diabetic kidney disease and reduce the risk of hospitalization for heart failure.”

Find the full press release on the Janssen website.

[email protected]

The Food and Drug Administration has approved canagliflozin (Invokana) for the treatment of diabetic kidney disease and for reduction of the risk of hospitalization for heart failure in patients with type 2 diabetes and diabetic kidney disease, which makes it the first drug indicated for diabetic kidney disease treatment in 20 years.

FDA approval, which was announced in a press release by Janssen, the drug’s manufacturer, is based on results from the phase 3 CREDENCE trial. In that study patients with type 2 diabetes and chronic diabetic kidney disease received either 100 mg canagliflozin or placebo. Patients who received canagliflozin experienced a 30% reduction in the risk of the primary composite endpoint, which included end-stage kidney disease, doubling of serum creatinine, and renal or cardiovascular death. The risk of secondary outcomes were also reduced in patients receiving canagliflozin, including a 39% reduction in the risk of hospitalization for heart failure.

The most common adverse events associated with canagliflozin, according to the label, are female genital mycotic infections, urinary tract infection, and increased urination. Serious adverse events associated with canagliflozin include ketoacidosis, kidney problems, serious urinary tract infections, hypoglycemia, necrotizing fasciitis, serious allergic reaction, and bone fractures.

“The real battle to turn the tide on kidney disease is in early detection and slowing its progression so that patients stay healthier and fewer patients reach kidney failure,” LaVerne A. Burton, president and CEO of the American Kidney Fund, said in the press release. “We are so grateful that advances in kidney disease research are producing treatment options that help to slow the progression of diabetic kidney disease and reduce the risk of hospitalization for heart failure.”

Find the full press release on the Janssen website.

[email protected]

Application of diluted apple cider vinegar (0.5% acetic acid) had no long term effects on the skin of patients with atopic dermatitis (AD), in a pilot split-arm study.

Madeleine_Steinbach/Getty Images

The aim of the study was to evaluate the effects of diluted apple cider vinegar application on transepidermal water loss (TEWL) and pH on skin affected by AD and on healthy skin, according to Lydia A. Luu of the department of dermatology at University of Virginia, Charlottesville, and colleagues. “Acetic acid, particularly apple cider vinegar, is prominent among emerging natural remedies used in AD. Therefore, determining the safety of this commonly used product is crucial,” they wrote in the study, published in Pediatric Dermatology.

In total, 11 patients with AD and 11 healthy controls were included; most of those with AD were considered mild (36.4%) or moderate (45.5%). Participants had not used systemic or topical antimicrobial treatments in the month preceding the study, and they were aged 12 years and older (mean ages were 20.6 years in the AD group and 28.8 years among controls). Those with AD had significantly elevated TEWL at baseline, compared with controls.

For 14 days, study participants soaked one forearm in dilute apple cider vinegar (0.5% acetic acid) and the other in tap water for 10 minutes daily. Changes in pH and TEWL before and after application were measured.

The researchers found that TEWL significantly increased immediately post treatment (at 0 and 15 minutes) in both groups, dropping to baseline at 30 minutes among those with AD and at 60 minutes among controls.

Skin pH was similar in both groups at baseline (4.86-4.88). After the cider vinegar soak, there was a transient reduction in skin pH among AD patients that lasted for 15 minutes among those with AD and 60 minutes in controls. This finding “suggests temporary acidification of the skin that has theoretical benefit of correcting disrupted skin pH in AD,” the authors wrote, noting that increased TEWL and alkaline skin pH is common among people with AD because of skin barrier dysfunction.

With respect to safety, 72.7% (16) of the participants experienced skin discomfort, mostly described as mild, limited to the vinegar-treated arm. After discontinuation, the majority of skin irritation resolved quickly, with no additional therapy.

The authors acknowledged two key limitations of the study were the homogeneous patient population and small sample size. “Although epidermal acidification would theoretically be beneficial in treating AD, our study shows that acidification by way of topical bathing in a 0.5% [apple cider vinegar] solution as performed in this study is not useful in AD treatment,” they wrote. “Further studies in a more diverse population will be necessary to fully characterize the risk/benefit profile of topical dilute apple cider vinegar treatments.”

The study was funded by the University of Virginia. The authors did not provide information on financial disclosures.

SOURCE: Luu LA et al. Pediatr Dermatol. 2019 Jul 22. doi: 10.1111/pde.13888.

Application of diluted apple cider vinegar (0.5% acetic acid) had no long term effects on the skin of patients with atopic dermatitis (AD), in a pilot split-arm study.

Madeleine_Steinbach/Getty Images

The aim of the study was to evaluate the effects of diluted apple cider vinegar application on transepidermal water loss (TEWL) and pH on skin affected by AD and on healthy skin, according to Lydia A. Luu of the department of dermatology at University of Virginia, Charlottesville, and colleagues. “Acetic acid, particularly apple cider vinegar, is prominent among emerging natural remedies used in AD. Therefore, determining the safety of this commonly used product is crucial,” they wrote in the study, published in Pediatric Dermatology.

In total, 11 patients with AD and 11 healthy controls were included; most of those with AD were considered mild (36.4%) or moderate (45.5%). Participants had not used systemic or topical antimicrobial treatments in the month preceding the study, and they were aged 12 years and older (mean ages were 20.6 years in the AD group and 28.8 years among controls). Those with AD had significantly elevated TEWL at baseline, compared with controls.

For 14 days, study participants soaked one forearm in dilute apple cider vinegar (0.5% acetic acid) and the other in tap water for 10 minutes daily. Changes in pH and TEWL before and after application were measured.

The researchers found that TEWL significantly increased immediately post treatment (at 0 and 15 minutes) in both groups, dropping to baseline at 30 minutes among those with AD and at 60 minutes among controls.

Skin pH was similar in both groups at baseline (4.86-4.88). After the cider vinegar soak, there was a transient reduction in skin pH among AD patients that lasted for 15 minutes among those with AD and 60 minutes in controls. This finding “suggests temporary acidification of the skin that has theoretical benefit of correcting disrupted skin pH in AD,” the authors wrote, noting that increased TEWL and alkaline skin pH is common among people with AD because of skin barrier dysfunction.

With respect to safety, 72.7% (16) of the participants experienced skin discomfort, mostly described as mild, limited to the vinegar-treated arm. After discontinuation, the majority of skin irritation resolved quickly, with no additional therapy.

The authors acknowledged two key limitations of the study were the homogeneous patient population and small sample size. “Although epidermal acidification would theoretically be beneficial in treating AD, our study shows that acidification by way of topical bathing in a 0.5% [apple cider vinegar] solution as performed in this study is not useful in AD treatment,” they wrote. “Further studies in a more diverse population will be necessary to fully characterize the risk/benefit profile of topical dilute apple cider vinegar treatments.”

The study was funded by the University of Virginia. The authors did not provide information on financial disclosures.

SOURCE: Luu LA et al. Pediatr Dermatol. 2019 Jul 22. doi: 10.1111/pde.13888.

Application of diluted apple cider vinegar (0.5% acetic acid) had no long term effects on the skin of patients with atopic dermatitis (AD), in a pilot split-arm study.

Madeleine_Steinbach/Getty Images

The aim of the study was to evaluate the effects of diluted apple cider vinegar application on transepidermal water loss (TEWL) and pH on skin affected by AD and on healthy skin, according to Lydia A. Luu of the department of dermatology at University of Virginia, Charlottesville, and colleagues. “Acetic acid, particularly apple cider vinegar, is prominent among emerging natural remedies used in AD. Therefore, determining the safety of this commonly used product is crucial,” they wrote in the study, published in Pediatric Dermatology.

In total, 11 patients with AD and 11 healthy controls were included; most of those with AD were considered mild (36.4%) or moderate (45.5%). Participants had not used systemic or topical antimicrobial treatments in the month preceding the study, and they were aged 12 years and older (mean ages were 20.6 years in the AD group and 28.8 years among controls). Those with AD had significantly elevated TEWL at baseline, compared with controls.

For 14 days, study participants soaked one forearm in dilute apple cider vinegar (0.5% acetic acid) and the other in tap water for 10 minutes daily. Changes in pH and TEWL before and after application were measured.

The researchers found that TEWL significantly increased immediately post treatment (at 0 and 15 minutes) in both groups, dropping to baseline at 30 minutes among those with AD and at 60 minutes among controls.

Skin pH was similar in both groups at baseline (4.86-4.88). After the cider vinegar soak, there was a transient reduction in skin pH among AD patients that lasted for 15 minutes among those with AD and 60 minutes in controls. This finding “suggests temporary acidification of the skin that has theoretical benefit of correcting disrupted skin pH in AD,” the authors wrote, noting that increased TEWL and alkaline skin pH is common among people with AD because of skin barrier dysfunction.

With respect to safety, 72.7% (16) of the participants experienced skin discomfort, mostly described as mild, limited to the vinegar-treated arm. After discontinuation, the majority of skin irritation resolved quickly, with no additional therapy.

The authors acknowledged two key limitations of the study were the homogeneous patient population and small sample size. “Although epidermal acidification would theoretically be beneficial in treating AD, our study shows that acidification by way of topical bathing in a 0.5% [apple cider vinegar] solution as performed in this study is not useful in AD treatment,” they wrote. “Further studies in a more diverse population will be necessary to fully characterize the risk/benefit profile of topical dilute apple cider vinegar treatments.”

The study was funded by the University of Virginia. The authors did not provide information on financial disclosures.

SOURCE: Luu LA et al. Pediatr Dermatol. 2019 Jul 22. doi: 10.1111/pde.13888.

Four genetic variations appear to link psychotic experiences with other psychiatric disorders, including schizophrenia, major depressive disorder, bipolar disorder, and neurodevelopmental disorders, a large genetic study has concluded.

The findings suggest that psychotic experiences might not be specifically driven by schizophrenia but instead are associated with a generally increased risk for a mental health disorder, reported Sophie E. Legge, PhD, and colleagues. Their study was published in JAMA Psychiatry.

Although it is informative, the study is unlikely to expand the knowledge of schizophrenia-specific genetics.

“Consistent with other studies, the heritability estimate (1.71%) was low, and given that the variance explained in our polygenic risk analysis was also low, the finding suggests that understanding the genetics of psychotic experiences is unlikely to have an important effect on understanding the genetics of schizophrenia specifically,” wrote Dr. Legge, of the MRC Center for Neuropsychiatric Genetics and Genomics in the division of psychological medicine and clinical neurosciences at Cardiff (Wales) University, and colleagues.

The team conducted a genomewide association study (GWAS) using data from 127,966 individuals in the U.K. Biobank. Of these, 6,123 reported any psychotic experience, 2,143 reported distressing psychotic experiences, and 3,337 reported multiple experiences. The remainder served as controls. At the time of the biobank data collection, the subjects were a mean of 64 years of age; 56% were women.

First psychotic experience occurred at a mean of almost 32 years of age, but about a third reported that the first episode occurred before age 20, or that psychotic experiences had been happening ever since they could remember. Another third reported their first experience between ages 40 and 76 years.

The investigators conducted three GWAS studies: one for any psychotic experience, one for distressing experiences, and one for multiple experiences.

No significant genetic associations were found among those with multiple psychotic experiences, the authors said.

But they did find four variants significantly associated with the other experience categories.

Two variants were associated with any psychotic experience. Those with rs10994278, an intronic variant within Ankyrin-3 (ANK3), were 16% more likely to have a psychotic experience (odds ratio, 1.16). Those with intergenic variant rs549656827 were 39% less likely (OR, 0.61). “The ANK3 gene encodes ankyrin-G, a protein that has been shown to regulate the assembly of voltage-gated sodium channels and is essential for normal synaptic function,” the authors said. “ANK3 is one of strongest and most replicated genes for bipolar disorder, and variants within ANK3 have also been associated in the Psychiatric Genomics Consortium cross-disorder GWAS, and in a rare variant analysis of autism spectrum disorder.”

Two variants were linked to distressing psychotic experiences: rs75459873, intronic to cannabinoid receptor 2 (CNR2), decreased the risk by 34% (OR, 0.66). Intergenic variant rs3849810 increased the risk by 12% (OR, 1.12).

“CNR2 encodes for CB2, one of two well-characterized cannabinoid receptors. Several lines of evidence have implicated the endocannabinoid system in psychiatric disorders, including schizophrenia and depression. The main psychoactive agent of cannabis, tetrahydrocannabinol, can cause acute psychotic symptoms and cognitive impairment. Given that cannabis use is strongly associated with psychotic experiences, we tested, but found no evidence for, a mediating or moderating effect of cannabis use on the association of rs75459873 and distressing psychotic experiences. However, while no evidence was found in this study, a mediating effect of cannabis use cannot be ruled out given the relatively low power of such analyses and the potential measurement error.”

Also, significant genetic correlations were found between any psychotic experiences and major depressive disorder, autism spectrum disorder, ADHD, and schizophrenia. However, the polygenic risk scores for schizophrenia, major depressive disorder, bipolar disorder, ADHD, and autism spectrum disorder, were low.

“We also considered individual psychotic symptoms and found that polygenic risk scores for schizophrenia, bipolar disorder, depression, and ADHD were more strongly associated with delusions of persecution than with the other psychotic symptoms.”

Those with distressing psychotic experiences tended to have more copy number variations (CNVs) associated with schizophrenia (OR, 2.04) and neurodevelopmental disorders (OR, 1.75). The team also found significant associations between distressing experiences and major depressive disorder, ADHD, autism spectrum disorder, and schizophrenia.

“We found particular enrichment of these [polygenic risk scores] in distressing psychotic experiences and for delusions of persecution,” they noted. “ ... All schizophrenia-associated [copy number variations] are also associated with neurodevelopmental disorders such as intellectual disability and autism.”

The study’s strengths include its large sample size. Among its limitations, the researchers said, are the study’s retrospective measurement of psychotic experiences based on self-report from a questionnaire that was online. Gathering the data in that way raised the likelihood of possible error, they said.

Dr. Legge reported having no disclosures.

[email protected]

SOURCE: Legge SE et al. JAMA Psychiatry. 2019 Sep 25. doi: 10.1001/jamapsychiatry.2019.2508.

Four genetic variations appear to link psychotic experiences with other psychiatric disorders, including schizophrenia, major depressive disorder, bipolar disorder, and neurodevelopmental disorders, a large genetic study has concluded.

The findings suggest that psychotic experiences might not be specifically driven by schizophrenia but instead are associated with a generally increased risk for a mental health disorder, reported Sophie E. Legge, PhD, and colleagues. Their study was published in JAMA Psychiatry.

Although it is informative, the study is unlikely to expand the knowledge of schizophrenia-specific genetics.

“Consistent with other studies, the heritability estimate (1.71%) was low, and given that the variance explained in our polygenic risk analysis was also low, the finding suggests that understanding the genetics of psychotic experiences is unlikely to have an important effect on understanding the genetics of schizophrenia specifically,” wrote Dr. Legge, of the MRC Center for Neuropsychiatric Genetics and Genomics in the division of psychological medicine and clinical neurosciences at Cardiff (Wales) University, and colleagues.

The team conducted a genomewide association study (GWAS) using data from 127,966 individuals in the U.K. Biobank. Of these, 6,123 reported any psychotic experience, 2,143 reported distressing psychotic experiences, and 3,337 reported multiple experiences. The remainder served as controls. At the time of the biobank data collection, the subjects were a mean of 64 years of age; 56% were women.

First psychotic experience occurred at a mean of almost 32 years of age, but about a third reported that the first episode occurred before age 20, or that psychotic experiences had been happening ever since they could remember. Another third reported their first experience between ages 40 and 76 years.

The investigators conducted three GWAS studies: one for any psychotic experience, one for distressing experiences, and one for multiple experiences.

No significant genetic associations were found among those with multiple psychotic experiences, the authors said.

But they did find four variants significantly associated with the other experience categories.

Two variants were associated with any psychotic experience. Those with rs10994278, an intronic variant within Ankyrin-3 (ANK3), were 16% more likely to have a psychotic experience (odds ratio, 1.16). Those with intergenic variant rs549656827 were 39% less likely (OR, 0.61). “The ANK3 gene encodes ankyrin-G, a protein that has been shown to regulate the assembly of voltage-gated sodium channels and is essential for normal synaptic function,” the authors said. “ANK3 is one of strongest and most replicated genes for bipolar disorder, and variants within ANK3 have also been associated in the Psychiatric Genomics Consortium cross-disorder GWAS, and in a rare variant analysis of autism spectrum disorder.”

Two variants were linked to distressing psychotic experiences: rs75459873, intronic to cannabinoid receptor 2 (CNR2), decreased the risk by 34% (OR, 0.66). Intergenic variant rs3849810 increased the risk by 12% (OR, 1.12).

“CNR2 encodes for CB2, one of two well-characterized cannabinoid receptors. Several lines of evidence have implicated the endocannabinoid system in psychiatric disorders, including schizophrenia and depression. The main psychoactive agent of cannabis, tetrahydrocannabinol, can cause acute psychotic symptoms and cognitive impairment. Given that cannabis use is strongly associated with psychotic experiences, we tested, but found no evidence for, a mediating or moderating effect of cannabis use on the association of rs75459873 and distressing psychotic experiences. However, while no evidence was found in this study, a mediating effect of cannabis use cannot be ruled out given the relatively low power of such analyses and the potential measurement error.”

Also, significant genetic correlations were found between any psychotic experiences and major depressive disorder, autism spectrum disorder, ADHD, and schizophrenia. However, the polygenic risk scores for schizophrenia, major depressive disorder, bipolar disorder, ADHD, and autism spectrum disorder, were low.

“We also considered individual psychotic symptoms and found that polygenic risk scores for schizophrenia, bipolar disorder, depression, and ADHD were more strongly associated with delusions of persecution than with the other psychotic symptoms.”

Those with distressing psychotic experiences tended to have more copy number variations (CNVs) associated with schizophrenia (OR, 2.04) and neurodevelopmental disorders (OR, 1.75). The team also found significant associations between distressing experiences and major depressive disorder, ADHD, autism spectrum disorder, and schizophrenia.

“We found particular enrichment of these [polygenic risk scores] in distressing psychotic experiences and for delusions of persecution,” they noted. “ ... All schizophrenia-associated [copy number variations] are also associated with neurodevelopmental disorders such as intellectual disability and autism.”

The study’s strengths include its large sample size. Among its limitations, the researchers said, are the study’s retrospective measurement of psychotic experiences based on self-report from a questionnaire that was online. Gathering the data in that way raised the likelihood of possible error, they said.

Dr. Legge reported having no disclosures.

[email protected]

SOURCE: Legge SE et al. JAMA Psychiatry. 2019 Sep 25. doi: 10.1001/jamapsychiatry.2019.2508.

Four genetic variations appear to link psychotic experiences with other psychiatric disorders, including schizophrenia, major depressive disorder, bipolar disorder, and neurodevelopmental disorders, a large genetic study has concluded.

The findings suggest that psychotic experiences might not be specifically driven by schizophrenia but instead are associated with a generally increased risk for a mental health disorder, reported Sophie E. Legge, PhD, and colleagues. Their study was published in JAMA Psychiatry.

Although it is informative, the study is unlikely to expand the knowledge of schizophrenia-specific genetics.

“Consistent with other studies, the heritability estimate (1.71%) was low, and given that the variance explained in our polygenic risk analysis was also low, the finding suggests that understanding the genetics of psychotic experiences is unlikely to have an important effect on understanding the genetics of schizophrenia specifically,” wrote Dr. Legge, of the MRC Center for Neuropsychiatric Genetics and Genomics in the division of psychological medicine and clinical neurosciences at Cardiff (Wales) University, and colleagues.

The team conducted a genomewide association study (GWAS) using data from 127,966 individuals in the U.K. Biobank. Of these, 6,123 reported any psychotic experience, 2,143 reported distressing psychotic experiences, and 3,337 reported multiple experiences. The remainder served as controls. At the time of the biobank data collection, the subjects were a mean of 64 years of age; 56% were women.

First psychotic experience occurred at a mean of almost 32 years of age, but about a third reported that the first episode occurred before age 20, or that psychotic experiences had been happening ever since they could remember. Another third reported their first experience between ages 40 and 76 years.

The investigators conducted three GWAS studies: one for any psychotic experience, one for distressing experiences, and one for multiple experiences.

No significant genetic associations were found among those with multiple psychotic experiences, the authors said.

But they did find four variants significantly associated with the other experience categories.

Two variants were associated with any psychotic experience. Those with rs10994278, an intronic variant within Ankyrin-3 (ANK3), were 16% more likely to have a psychotic experience (odds ratio, 1.16). Those with intergenic variant rs549656827 were 39% less likely (OR, 0.61). “The ANK3 gene encodes ankyrin-G, a protein that has been shown to regulate the assembly of voltage-gated sodium channels and is essential for normal synaptic function,” the authors said. “ANK3 is one of strongest and most replicated genes for bipolar disorder, and variants within ANK3 have also been associated in the Psychiatric Genomics Consortium cross-disorder GWAS, and in a rare variant analysis of autism spectrum disorder.”

Two variants were linked to distressing psychotic experiences: rs75459873, intronic to cannabinoid receptor 2 (CNR2), decreased the risk by 34% (OR, 0.66). Intergenic variant rs3849810 increased the risk by 12% (OR, 1.12).

“CNR2 encodes for CB2, one of two well-characterized cannabinoid receptors. Several lines of evidence have implicated the endocannabinoid system in psychiatric disorders, including schizophrenia and depression. The main psychoactive agent of cannabis, tetrahydrocannabinol, can cause acute psychotic symptoms and cognitive impairment. Given that cannabis use is strongly associated with psychotic experiences, we tested, but found no evidence for, a mediating or moderating effect of cannabis use on the association of rs75459873 and distressing psychotic experiences. However, while no evidence was found in this study, a mediating effect of cannabis use cannot be ruled out given the relatively low power of such analyses and the potential measurement error.”

Also, significant genetic correlations were found between any psychotic experiences and major depressive disorder, autism spectrum disorder, ADHD, and schizophrenia. However, the polygenic risk scores for schizophrenia, major depressive disorder, bipolar disorder, ADHD, and autism spectrum disorder, were low.

“We also considered individual psychotic symptoms and found that polygenic risk scores for schizophrenia, bipolar disorder, depression, and ADHD were more strongly associated with delusions of persecution than with the other psychotic symptoms.”

Those with distressing psychotic experiences tended to have more copy number variations (CNVs) associated with schizophrenia (OR, 2.04) and neurodevelopmental disorders (OR, 1.75). The team also found significant associations between distressing experiences and major depressive disorder, ADHD, autism spectrum disorder, and schizophrenia.

“We found particular enrichment of these [polygenic risk scores] in distressing psychotic experiences and for delusions of persecution,” they noted. “ ... All schizophrenia-associated [copy number variations] are also associated with neurodevelopmental disorders such as intellectual disability and autism.”

The study’s strengths include its large sample size. Among its limitations, the researchers said, are the study’s retrospective measurement of psychotic experiences based on self-report from a questionnaire that was online. Gathering the data in that way raised the likelihood of possible error, they said.

Dr. Legge reported having no disclosures.

[email protected]

SOURCE: Legge SE et al. JAMA Psychiatry. 2019 Sep 25. doi: 10.1001/jamapsychiatry.2019.2508.

In this edition of “How I will treat my next patient,” I highlight three studies presented at the World Conference on Lung Cancer (WCLC 2019) regarding the use of tissue biomarkers to predict benefit when immune checkpoint inhibitors (ICIs) are combined with chemotherapy in the treatment of stage IV non–small cell lung cancer (NSCLC) patients.

TMB in nonsquamous NSCLC

Marina C. Garassino, MD, and colleagues examined tumor mutation burden (TMB) to predict benefit from pembrolizumab in the KEYNOTE-189 study. KEYNOTE-189 was a double-blind comparison of first-line chemotherapy plus either pembrolizumab or placebo in 616 patients with stage IV nonsquamous NSCLC who were randomized 2:1 to the treatment arms.

Overall, adding pembrolizumab to pemetrexed and platinum significantly improved overall survival (hazard ratio, 0.49), progression-free survival (HR, 0.52), and overall response rate (47.6% vs. 18.9%). Benefit was observed in all analyzed subgroups, including patients with programmed death-ligand 1 (PD-L1) of less than 1%, 1%-49%, and 50% or greater.

In 293 patients – less than 50% of the total participants in the trial – with evaluable TMB data, TMB as a continuous variable showed no significant association with overall survival, progression-free survival, or overall response rate. There was no cut point at which TMB predicted outcome from treatment.

Similarly, Corey Langer, MD, and colleagues presented an exploratory analysis of the randomized, phase 2 KEYNOTE-021 trial (open label, pembrolizumab plus chemotherapy in 70 stage IV nonsquamous NSCLC patients). There was no association between tissue TMB and overall survival, progression-free survival, or overall response rate. In patients with tissue TMB greater than 175 mutations/exome and less than 175 mutations/exome, the overall response rate was 71% and 61%, respectively.

Both presenters recommended that tissue TMB not yet be used in therapeutic decision making.

How these results influence clinical practice

TMB has been associated with response to ICIs, but there is little information regarding whether TMB predicts for response to chemotherapy, either given alone or with ICIs. Logistical issues have limited the clinical utility of TMB. There are a variety of methodologies to measure TMB and no consensus on the ideal cut point for defining benefit from ICI therapy.

While TMB remains a marker of interest, the two presentations at WCLC 2019 demonstrate that additional research is needed to define whether TMB needs to be combined with other markers in an algorithm or matrix to guide decision making or whether we should focus entirely on identifying better biomarkers of immunogenicity.

PD-L1 expression and overall survival

Federico Cappuzzo, MD, and colleagues reported a subset analysis of IMpower131, a randomized, phase 3 trial of chemotherapy plus or minus atezolizumab as first-line therapy in 1,021 patients with stage IV squamous NSCLC. Patients were randomized to arm A (atezolizumab plus carboplatin plus paclitaxel), arm B (atezolizumab plus carboplatin plus nab-paclitaxel) or arm C (carboplatin plus nab-paclitaxel). Investigator-assessed progression-free survival, reported at the 2018 annual meeting of the American Society of Clinical Oncology, showed a small (about 21 days), but statistically significant, improvement in median progression-free survival in arm B versus arm C. The progression-free survival benefit was seen in all PD-L1-positive subgroups. At WCLC 2019, he reported the final overall survival results of arms B versus C.

Median overall survival in the intent-to-treat population was 14.2 months with atezolizumab versus 13.5 months without it (HR, 0.88). Patients with high PD-L1 expression (14% and 13% of patients in the groups, respectively), experienced dramatic, clinically important improvement in overall survival with atezolizumab plus chemotherapy, compared with chemotherapy alone (median of 23.4 vs. 10.2 months; HR, 0.48).

In IMpower 131, PD-L1-high expression was defined as TC3 or IC3 – expression on greater than 50% of tumor cells or greater than 10% of immune cells. Patients were also categorized as PD-L1 positive (TC 1/2/3 or IC 1/2/3 – expression of PD-L1 on 1% or greater of tumor cells or immune cells) or PD-LI negative (TC 0 or IC 0 – expression on less than 1% of cells). The PD-L1-positive and negative subsets did not demonstrate improved overall survival with atezolizumab.

How these results influence clinical practice

As noted above, in NSCLC patients (regardless of histology), we need biomarkers that predict benefit from ICIs alone and additive benefit when ICIs are combined with other, potentially toxic therapies. In the subset analysis of IMpower 131, despite clinically relevant differences in overall survival for the “PD-L1-high” patients, the PD-L1-positive patients did not benefit, so PD-L1 tumor proportion score remains an imperfect biomarker.

To put this report in its proper context, it will be important to analyze the details of the final manuscript of IMpower 131, particularly the comparison of arms A plus B versus C and the proportion of arm C patients who ultimately received an ICI in the second- or later-line setting. In the meantime, clinicians will select their ICI and chemotherapy regimen of choice, utilizing PD-L1 expression as an “eyebrow raiser,” but not an exclusionary criteria – as they did prior to WCLC 2019.

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.

In this edition of “How I will treat my next patient,” I highlight three studies presented at the World Conference on Lung Cancer (WCLC 2019) regarding the use of tissue biomarkers to predict benefit when immune checkpoint inhibitors (ICIs) are combined with chemotherapy in the treatment of stage IV non–small cell lung cancer (NSCLC) patients.

TMB in nonsquamous NSCLC

Marina C. Garassino, MD, and colleagues examined tumor mutation burden (TMB) to predict benefit from pembrolizumab in the KEYNOTE-189 study. KEYNOTE-189 was a double-blind comparison of first-line chemotherapy plus either pembrolizumab or placebo in 616 patients with stage IV nonsquamous NSCLC who were randomized 2:1 to the treatment arms.

Overall, adding pembrolizumab to pemetrexed and platinum significantly improved overall survival (hazard ratio, 0.49), progression-free survival (HR, 0.52), and overall response rate (47.6% vs. 18.9%). Benefit was observed in all analyzed subgroups, including patients with programmed death-ligand 1 (PD-L1) of less than 1%, 1%-49%, and 50% or greater.

In 293 patients – less than 50% of the total participants in the trial – with evaluable TMB data, TMB as a continuous variable showed no significant association with overall survival, progression-free survival, or overall response rate. There was no cut point at which TMB predicted outcome from treatment.

Similarly, Corey Langer, MD, and colleagues presented an exploratory analysis of the randomized, phase 2 KEYNOTE-021 trial (open label, pembrolizumab plus chemotherapy in 70 stage IV nonsquamous NSCLC patients). There was no association between tissue TMB and overall survival, progression-free survival, or overall response rate. In patients with tissue TMB greater than 175 mutations/exome and less than 175 mutations/exome, the overall response rate was 71% and 61%, respectively.

Both presenters recommended that tissue TMB not yet be used in therapeutic decision making.

How these results influence clinical practice

TMB has been associated with response to ICIs, but there is little information regarding whether TMB predicts for response to chemotherapy, either given alone or with ICIs. Logistical issues have limited the clinical utility of TMB. There are a variety of methodologies to measure TMB and no consensus on the ideal cut point for defining benefit from ICI therapy.

While TMB remains a marker of interest, the two presentations at WCLC 2019 demonstrate that additional research is needed to define whether TMB needs to be combined with other markers in an algorithm or matrix to guide decision making or whether we should focus entirely on identifying better biomarkers of immunogenicity.

PD-L1 expression and overall survival

Federico Cappuzzo, MD, and colleagues reported a subset analysis of IMpower131, a randomized, phase 3 trial of chemotherapy plus or minus atezolizumab as first-line therapy in 1,021 patients with stage IV squamous NSCLC. Patients were randomized to arm A (atezolizumab plus carboplatin plus paclitaxel), arm B (atezolizumab plus carboplatin plus nab-paclitaxel) or arm C (carboplatin plus nab-paclitaxel). Investigator-assessed progression-free survival, reported at the 2018 annual meeting of the American Society of Clinical Oncology, showed a small (about 21 days), but statistically significant, improvement in median progression-free survival in arm B versus arm C. The progression-free survival benefit was seen in all PD-L1-positive subgroups. At WCLC 2019, he reported the final overall survival results of arms B versus C.

Median overall survival in the intent-to-treat population was 14.2 months with atezolizumab versus 13.5 months without it (HR, 0.88). Patients with high PD-L1 expression (14% and 13% of patients in the groups, respectively), experienced dramatic, clinically important improvement in overall survival with atezolizumab plus chemotherapy, compared with chemotherapy alone (median of 23.4 vs. 10.2 months; HR, 0.48).

In IMpower 131, PD-L1-high expression was defined as TC3 or IC3 – expression on greater than 50% of tumor cells or greater than 10% of immune cells. Patients were also categorized as PD-L1 positive (TC 1/2/3 or IC 1/2/3 – expression of PD-L1 on 1% or greater of tumor cells or immune cells) or PD-LI negative (TC 0 or IC 0 – expression on less than 1% of cells). The PD-L1-positive and negative subsets did not demonstrate improved overall survival with atezolizumab.

How these results influence clinical practice

As noted above, in NSCLC patients (regardless of histology), we need biomarkers that predict benefit from ICIs alone and additive benefit when ICIs are combined with other, potentially toxic therapies. In the subset analysis of IMpower 131, despite clinically relevant differences in overall survival for the “PD-L1-high” patients, the PD-L1-positive patients did not benefit, so PD-L1 tumor proportion score remains an imperfect biomarker.

To put this report in its proper context, it will be important to analyze the details of the final manuscript of IMpower 131, particularly the comparison of arms A plus B versus C and the proportion of arm C patients who ultimately received an ICI in the second- or later-line setting. In the meantime, clinicians will select their ICI and chemotherapy regimen of choice, utilizing PD-L1 expression as an “eyebrow raiser,” but not an exclusionary criteria – as they did prior to WCLC 2019.

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.

In this edition of “How I will treat my next patient,” I highlight three studies presented at the World Conference on Lung Cancer (WCLC 2019) regarding the use of tissue biomarkers to predict benefit when immune checkpoint inhibitors (ICIs) are combined with chemotherapy in the treatment of stage IV non–small cell lung cancer (NSCLC) patients.

TMB in nonsquamous NSCLC

Marina C. Garassino, MD, and colleagues examined tumor mutation burden (TMB) to predict benefit from pembrolizumab in the KEYNOTE-189 study. KEYNOTE-189 was a double-blind comparison of first-line chemotherapy plus either pembrolizumab or placebo in 616 patients with stage IV nonsquamous NSCLC who were randomized 2:1 to the treatment arms.

Overall, adding pembrolizumab to pemetrexed and platinum significantly improved overall survival (hazard ratio, 0.49), progression-free survival (HR, 0.52), and overall response rate (47.6% vs. 18.9%). Benefit was observed in all analyzed subgroups, including patients with programmed death-ligand 1 (PD-L1) of less than 1%, 1%-49%, and 50% or greater.

In 293 patients – less than 50% of the total participants in the trial – with evaluable TMB data, TMB as a continuous variable showed no significant association with overall survival, progression-free survival, or overall response rate. There was no cut point at which TMB predicted outcome from treatment.

Similarly, Corey Langer, MD, and colleagues presented an exploratory analysis of the randomized, phase 2 KEYNOTE-021 trial (open label, pembrolizumab plus chemotherapy in 70 stage IV nonsquamous NSCLC patients). There was no association between tissue TMB and overall survival, progression-free survival, or overall response rate. In patients with tissue TMB greater than 175 mutations/exome and less than 175 mutations/exome, the overall response rate was 71% and 61%, respectively.

Both presenters recommended that tissue TMB not yet be used in therapeutic decision making.

How these results influence clinical practice

TMB has been associated with response to ICIs, but there is little information regarding whether TMB predicts for response to chemotherapy, either given alone or with ICIs. Logistical issues have limited the clinical utility of TMB. There are a variety of methodologies to measure TMB and no consensus on the ideal cut point for defining benefit from ICI therapy.

While TMB remains a marker of interest, the two presentations at WCLC 2019 demonstrate that additional research is needed to define whether TMB needs to be combined with other markers in an algorithm or matrix to guide decision making or whether we should focus entirely on identifying better biomarkers of immunogenicity.

PD-L1 expression and overall survival

Federico Cappuzzo, MD, and colleagues reported a subset analysis of IMpower131, a randomized, phase 3 trial of chemotherapy plus or minus atezolizumab as first-line therapy in 1,021 patients with stage IV squamous NSCLC. Patients were randomized to arm A (atezolizumab plus carboplatin plus paclitaxel), arm B (atezolizumab plus carboplatin plus nab-paclitaxel) or arm C (carboplatin plus nab-paclitaxel). Investigator-assessed progression-free survival, reported at the 2018 annual meeting of the American Society of Clinical Oncology, showed a small (about 21 days), but statistically significant, improvement in median progression-free survival in arm B versus arm C. The progression-free survival benefit was seen in all PD-L1-positive subgroups. At WCLC 2019, he reported the final overall survival results of arms B versus C.

Median overall survival in the intent-to-treat population was 14.2 months with atezolizumab versus 13.5 months without it (HR, 0.88). Patients with high PD-L1 expression (14% and 13% of patients in the groups, respectively), experienced dramatic, clinically important improvement in overall survival with atezolizumab plus chemotherapy, compared with chemotherapy alone (median of 23.4 vs. 10.2 months; HR, 0.48).

In IMpower 131, PD-L1-high expression was defined as TC3 or IC3 – expression on greater than 50% of tumor cells or greater than 10% of immune cells. Patients were also categorized as PD-L1 positive (TC 1/2/3 or IC 1/2/3 – expression of PD-L1 on 1% or greater of tumor cells or immune cells) or PD-LI negative (TC 0 or IC 0 – expression on less than 1% of cells). The PD-L1-positive and negative subsets did not demonstrate improved overall survival with atezolizumab.

How these results influence clinical practice

As noted above, in NSCLC patients (regardless of histology), we need biomarkers that predict benefit from ICIs alone and additive benefit when ICIs are combined with other, potentially toxic therapies. In the subset analysis of IMpower 131, despite clinically relevant differences in overall survival for the “PD-L1-high” patients, the PD-L1-positive patients did not benefit, so PD-L1 tumor proportion score remains an imperfect biomarker.

To put this report in its proper context, it will be important to analyze the details of the final manuscript of IMpower 131, particularly the comparison of arms A plus B versus C and the proportion of arm C patients who ultimately received an ICI in the second- or later-line setting. In the meantime, clinicians will select their ICI and chemotherapy regimen of choice, utilizing PD-L1 expression as an “eyebrow raiser,” but not an exclusionary criteria – as they did prior to WCLC 2019.

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.

When an emergency department (ED) closes, neighboring hospitals—“bystander hospitals”—feel the effects, especially if they are already near or at full capacity: The health outcomes for their patients worsen, according to findings from a study funded by the National Heart, Lung, and Blood Institute (NHLBI).

The researchers examined outcomes for more than 1 million patients at nearly 4,000 hospitals in both urban and rural areas who had been affected by the closure or opening of an ED. The primary measures were 30-day, 90-day, and 1-year mortality rates, and 30-day readmission rates for heart attack. The researchers chose heart attacks because of the known benefits of timely treatment.

The researchers used changes in driving time between an ED and the next-closest one as a proxy for a closure or opening. If driving time increased, it meant a nearby ED had closed.

They found that when it took an additional 30 minutes or more to get to another hospital, the 1-year mortality rate in those receiving hospitals increased by 8% and the 30-day readmission rate by 6%. The likelihood of patients receiving an angioplasty or stent dropped by 4%.

However, the researchers also found that when an ED opened, the patients in the bystander hospitals benefited, experiencing a reduction in 1-year mortality by 5%. And the likelihood of their receiving percutaneous coronary intervention improved by 12%.

The study is believed to be the first to evaluate the impact of ED openings and closures on other hospitals. The lead author of the study, Renee Hsia, MD, said, “We now have evidence that hospital closures affect other hospitals, and they do so in different ways. Hospitals that are already crowded will likely be unable to maintain the same quality when a nearby emergency department closes.”

Limited resources at high-occupancy hospitals make them “sensitive to changes” in neighboring communities, the researchers say. “Hospital closures stress the health care infrastructure,” says Nicole Redmond, MD, PhD, MPH, a medical officer at NHLBI, “especially if the hospital is already caring for a socially and medically complex patient population and working at full capacity. As a result, such closures may inadvertently increase the health disparities that we are trying to mitigate.”

When an emergency department (ED) closes, neighboring hospitals—“bystander hospitals”—feel the effects, especially if they are already near or at full capacity: The health outcomes for their patients worsen, according to findings from a study funded by the National Heart, Lung, and Blood Institute (NHLBI).

The researchers examined outcomes for more than 1 million patients at nearly 4,000 hospitals in both urban and rural areas who had been affected by the closure or opening of an ED. The primary measures were 30-day, 90-day, and 1-year mortality rates, and 30-day readmission rates for heart attack. The researchers chose heart attacks because of the known benefits of timely treatment.

The researchers used changes in driving time between an ED and the next-closest one as a proxy for a closure or opening. If driving time increased, it meant a nearby ED had closed.

They found that when it took an additional 30 minutes or more to get to another hospital, the 1-year mortality rate in those receiving hospitals increased by 8% and the 30-day readmission rate by 6%. The likelihood of patients receiving an angioplasty or stent dropped by 4%.

However, the researchers also found that when an ED opened, the patients in the bystander hospitals benefited, experiencing a reduction in 1-year mortality by 5%. And the likelihood of their receiving percutaneous coronary intervention improved by 12%.

The study is believed to be the first to evaluate the impact of ED openings and closures on other hospitals. The lead author of the study, Renee Hsia, MD, said, “We now have evidence that hospital closures affect other hospitals, and they do so in different ways. Hospitals that are already crowded will likely be unable to maintain the same quality when a nearby emergency department closes.”

Limited resources at high-occupancy hospitals make them “sensitive to changes” in neighboring communities, the researchers say. “Hospital closures stress the health care infrastructure,” says Nicole Redmond, MD, PhD, MPH, a medical officer at NHLBI, “especially if the hospital is already caring for a socially and medically complex patient population and working at full capacity. As a result, such closures may inadvertently increase the health disparities that we are trying to mitigate.”

When an emergency department (ED) closes, neighboring hospitals—“bystander hospitals”—feel the effects, especially if they are already near or at full capacity: The health outcomes for their patients worsen, according to findings from a study funded by the National Heart, Lung, and Blood Institute (NHLBI).

The researchers examined outcomes for more than 1 million patients at nearly 4,000 hospitals in both urban and rural areas who had been affected by the closure or opening of an ED. The primary measures were 30-day, 90-day, and 1-year mortality rates, and 30-day readmission rates for heart attack. The researchers chose heart attacks because of the known benefits of timely treatment.

The researchers used changes in driving time between an ED and the next-closest one as a proxy for a closure or opening. If driving time increased, it meant a nearby ED had closed.

They found that when it took an additional 30 minutes or more to get to another hospital, the 1-year mortality rate in those receiving hospitals increased by 8% and the 30-day readmission rate by 6%. The likelihood of patients receiving an angioplasty or stent dropped by 4%.

However, the researchers also found that when an ED opened, the patients in the bystander hospitals benefited, experiencing a reduction in 1-year mortality by 5%. And the likelihood of their receiving percutaneous coronary intervention improved by 12%.

The study is believed to be the first to evaluate the impact of ED openings and closures on other hospitals. The lead author of the study, Renee Hsia, MD, said, “We now have evidence that hospital closures affect other hospitals, and they do so in different ways. Hospitals that are already crowded will likely be unable to maintain the same quality when a nearby emergency department closes.”

Limited resources at high-occupancy hospitals make them “sensitive to changes” in neighboring communities, the researchers say. “Hospital closures stress the health care infrastructure,” says Nicole Redmond, MD, PhD, MPH, a medical officer at NHLBI, “especially if the hospital is already caring for a socially and medically complex patient population and working at full capacity. As a result, such closures may inadvertently increase the health disparities that we are trying to mitigate.”