Jim Kling

SEATTLE – A novel treatment for amyotrophic lateral sclerosis (ALS) that targets brain cell energy production to promote remyelination showed signs of efficacy in a phase 2 trial, though it did not meet its primary endpoint, which was the change in the summated motor unit index (MUNIX) from baseline to week 36.

The drug, CNM-Au8, is being developed by Clene, and would represent a novel mechanism of action. “This is a brand-new approach. We used it complementary with riluzole and it was well tolerated, so I see this as an add-on therapy. I think if we can show some more positivity and longer-term results, it’s going to be a game changer for ALS,” Matthew Kiernan, MBBS, PhD, said in an interview. Dr. Kiernan presented the results at the 2022 annual meeting of the American Academy of Neurology.

Jim Kling/MDedge News

Riluzole (Rilutek), which received Food and Drug Administration approval in 1995, inhibits glutamate release to counter excitotoxicity, which is believed to play a role in ALS, Huntington’s disease, ischemia, and other acute and chronic neurodegenerative diseases. The other FDA-approved agent for ALS is the neuroprotective agent and free-radical scavenger edaravone (Radicava), approved in 2017.

CNM-Au8 is made up of catalytically active gold nanocrystals that cross the blood-brain barrier, but lacks the toxicity associated with other synthetic gold compounds, according to the company. The formulation is also being investigated for the treatment of Parkinson’s disease and multiple sclerosis. Basic research has shown that it stabilizes mitochondria and reduces accumulation of the TDP-43 protein, which is linked to spread of ALS through the brain, Dr. Kiernan said during his presentation.

The treatment is well tolerated. “Normally in an ALS trial, we see about a 25% dropout rate. There were no dropouts on the active compound in the clinical trial. There are less deaths, so improved survival,” said Dr. Kiernan, the Bushell chair of neurology at the University of Sydney and codirector of the Brain and Mind Center in Sydney.
 

Good safety signal

The fact that the trial missed its primary endpoint isn’t too concerning, according to Nicholas Johnson, MD, who comoderated the session where the study was presented. “ALS clinical trials are incredibly difficult to conduct, especially a phase 2 learning-phase clinical trial. At this phase, I’m much more buoyed by the fact that they have a good safety signal, and that they’re willing to move forward to that phase 3 clinical trial,” Dr. Johnson said in an interview. He is vice chair of research at Virginia Commonwealth University, Richmond.

A phase 3 clinical trial is in development in the United States and Europe. The drug also is included as part of the HEALEY ALS Platform Trial, which is testing multiple ALS therapies simultaneously. “The results from that should be available by the second half of this year and it will also inform us as to what the approach should be,” said Dr. Kiernan.

Dr. Johnson also was enthusiastic. “I’m excited to see the results in terms of the primary endpoints for that next phase 3 clinical trial,” he said.
 

Ongoing research

In September 2021, Clene announced a second expanded access program for people with ALS.

The study included a 36-week double-blind treatment period followed by long-term, open-label follow-up. Twenty-three patients received 30 mg CNM-Au8, and 22 received placebo. In the first 36 weeks, the treatment group was more likely to have no disease progression, defined as death, tracheostomy, noninvasive ventilation, or a gastronomy tube (P = .0125). The researchers compared the probability of experiencing a less than 6-point decline in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale. At 12 weeks, it was about 85% in both groups. At 24 weeks, it was about 60% to 50% in favor of the CNM-Au8 group, and at 36 weeks it was about 50% to 20% (P = .0350).

At 36 weeks, quality of life as measured by the ALS Specific Quality of Life–Short Form was better in the treatment group at 36 weeks (mean change, 0.9; P = .0177).

Survival was better in the treatment group at 96 weeks than the mortality derived from a European Network for the Cure of ALS prediction model (hazard ratio [HR], 0.2974; P = .0068). This benefit also was experienced by patients who received drug throughout the study (HR, 0.36; 95% confidence interval [CI], 0.12-1.1) and those who started out on placebo and converted to active drug during the open-label period (HR, 0.24; 95% CI, 0.064-0.88).

The study was funded by Clene and FightMND. Dr. Kiernan and Dr. Johnson have no relevant financial disclosures.

SEATTLE – A novel treatment for amyotrophic lateral sclerosis (ALS) that targets brain cell energy production to promote remyelination showed signs of efficacy in a phase 2 trial, though it did not meet its primary endpoint, which was the change in the summated motor unit index (MUNIX) from baseline to week 36.

The drug, CNM-Au8, is being developed by Clene, and would represent a novel mechanism of action. “This is a brand-new approach. We used it complementary with riluzole and it was well tolerated, so I see this as an add-on therapy. I think if we can show some more positivity and longer-term results, it’s going to be a game changer for ALS,” Matthew Kiernan, MBBS, PhD, said in an interview. Dr. Kiernan presented the results at the 2022 annual meeting of the American Academy of Neurology.

Jim Kling/MDedge News

Riluzole (Rilutek), which received Food and Drug Administration approval in 1995, inhibits glutamate release to counter excitotoxicity, which is believed to play a role in ALS, Huntington’s disease, ischemia, and other acute and chronic neurodegenerative diseases. The other FDA-approved agent for ALS is the neuroprotective agent and free-radical scavenger edaravone (Radicava), approved in 2017.

CNM-Au8 is made up of catalytically active gold nanocrystals that cross the blood-brain barrier, but lacks the toxicity associated with other synthetic gold compounds, according to the company. The formulation is also being investigated for the treatment of Parkinson’s disease and multiple sclerosis. Basic research has shown that it stabilizes mitochondria and reduces accumulation of the TDP-43 protein, which is linked to spread of ALS through the brain, Dr. Kiernan said during his presentation.

The treatment is well tolerated. “Normally in an ALS trial, we see about a 25% dropout rate. There were no dropouts on the active compound in the clinical trial. There are less deaths, so improved survival,” said Dr. Kiernan, the Bushell chair of neurology at the University of Sydney and codirector of the Brain and Mind Center in Sydney.
 

Good safety signal

The fact that the trial missed its primary endpoint isn’t too concerning, according to Nicholas Johnson, MD, who comoderated the session where the study was presented. “ALS clinical trials are incredibly difficult to conduct, especially a phase 2 learning-phase clinical trial. At this phase, I’m much more buoyed by the fact that they have a good safety signal, and that they’re willing to move forward to that phase 3 clinical trial,” Dr. Johnson said in an interview. He is vice chair of research at Virginia Commonwealth University, Richmond.

A phase 3 clinical trial is in development in the United States and Europe. The drug also is included as part of the HEALEY ALS Platform Trial, which is testing multiple ALS therapies simultaneously. “The results from that should be available by the second half of this year and it will also inform us as to what the approach should be,” said Dr. Kiernan.

Dr. Johnson also was enthusiastic. “I’m excited to see the results in terms of the primary endpoints for that next phase 3 clinical trial,” he said.
 

Ongoing research

In September 2021, Clene announced a second expanded access program for people with ALS.

The study included a 36-week double-blind treatment period followed by long-term, open-label follow-up. Twenty-three patients received 30 mg CNM-Au8, and 22 received placebo. In the first 36 weeks, the treatment group was more likely to have no disease progression, defined as death, tracheostomy, noninvasive ventilation, or a gastronomy tube (P = .0125). The researchers compared the probability of experiencing a less than 6-point decline in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale. At 12 weeks, it was about 85% in both groups. At 24 weeks, it was about 60% to 50% in favor of the CNM-Au8 group, and at 36 weeks it was about 50% to 20% (P = .0350).

At 36 weeks, quality of life as measured by the ALS Specific Quality of Life–Short Form was better in the treatment group at 36 weeks (mean change, 0.9; P = .0177).

Survival was better in the treatment group at 96 weeks than the mortality derived from a European Network for the Cure of ALS prediction model (hazard ratio [HR], 0.2974; P = .0068). This benefit also was experienced by patients who received drug throughout the study (HR, 0.36; 95% confidence interval [CI], 0.12-1.1) and those who started out on placebo and converted to active drug during the open-label period (HR, 0.24; 95% CI, 0.064-0.88).

The study was funded by Clene and FightMND. Dr. Kiernan and Dr. Johnson have no relevant financial disclosures.

SEATTLE – A novel treatment for amyotrophic lateral sclerosis (ALS) that targets brain cell energy production to promote remyelination showed signs of efficacy in a phase 2 trial, though it did not meet its primary endpoint, which was the change in the summated motor unit index (MUNIX) from baseline to week 36.

The drug, CNM-Au8, is being developed by Clene, and would represent a novel mechanism of action. “This is a brand-new approach. We used it complementary with riluzole and it was well tolerated, so I see this as an add-on therapy. I think if we can show some more positivity and longer-term results, it’s going to be a game changer for ALS,” Matthew Kiernan, MBBS, PhD, said in an interview. Dr. Kiernan presented the results at the 2022 annual meeting of the American Academy of Neurology.

Jim Kling/MDedge News

Riluzole (Rilutek), which received Food and Drug Administration approval in 1995, inhibits glutamate release to counter excitotoxicity, which is believed to play a role in ALS, Huntington’s disease, ischemia, and other acute and chronic neurodegenerative diseases. The other FDA-approved agent for ALS is the neuroprotective agent and free-radical scavenger edaravone (Radicava), approved in 2017.

CNM-Au8 is made up of catalytically active gold nanocrystals that cross the blood-brain barrier, but lacks the toxicity associated with other synthetic gold compounds, according to the company. The formulation is also being investigated for the treatment of Parkinson’s disease and multiple sclerosis. Basic research has shown that it stabilizes mitochondria and reduces accumulation of the TDP-43 protein, which is linked to spread of ALS through the brain, Dr. Kiernan said during his presentation.

The treatment is well tolerated. “Normally in an ALS trial, we see about a 25% dropout rate. There were no dropouts on the active compound in the clinical trial. There are less deaths, so improved survival,” said Dr. Kiernan, the Bushell chair of neurology at the University of Sydney and codirector of the Brain and Mind Center in Sydney.
 

Good safety signal

The fact that the trial missed its primary endpoint isn’t too concerning, according to Nicholas Johnson, MD, who comoderated the session where the study was presented. “ALS clinical trials are incredibly difficult to conduct, especially a phase 2 learning-phase clinical trial. At this phase, I’m much more buoyed by the fact that they have a good safety signal, and that they’re willing to move forward to that phase 3 clinical trial,” Dr. Johnson said in an interview. He is vice chair of research at Virginia Commonwealth University, Richmond.

A phase 3 clinical trial is in development in the United States and Europe. The drug also is included as part of the HEALEY ALS Platform Trial, which is testing multiple ALS therapies simultaneously. “The results from that should be available by the second half of this year and it will also inform us as to what the approach should be,” said Dr. Kiernan.

Dr. Johnson also was enthusiastic. “I’m excited to see the results in terms of the primary endpoints for that next phase 3 clinical trial,” he said.
 

Ongoing research

In September 2021, Clene announced a second expanded access program for people with ALS.

The study included a 36-week double-blind treatment period followed by long-term, open-label follow-up. Twenty-three patients received 30 mg CNM-Au8, and 22 received placebo. In the first 36 weeks, the treatment group was more likely to have no disease progression, defined as death, tracheostomy, noninvasive ventilation, or a gastronomy tube (P = .0125). The researchers compared the probability of experiencing a less than 6-point decline in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale. At 12 weeks, it was about 85% in both groups. At 24 weeks, it was about 60% to 50% in favor of the CNM-Au8 group, and at 36 weeks it was about 50% to 20% (P = .0350).

At 36 weeks, quality of life as measured by the ALS Specific Quality of Life–Short Form was better in the treatment group at 36 weeks (mean change, 0.9; P = .0177).

Survival was better in the treatment group at 96 weeks than the mortality derived from a European Network for the Cure of ALS prediction model (hazard ratio [HR], 0.2974; P = .0068). This benefit also was experienced by patients who received drug throughout the study (HR, 0.36; 95% confidence interval [CI], 0.12-1.1) and those who started out on placebo and converted to active drug during the open-label period (HR, 0.24; 95% CI, 0.064-0.88).

The study was funded by Clene and FightMND. Dr. Kiernan and Dr. Johnson have no relevant financial disclosures.

SEATTLE – Use of antiseizure medications while breastfeeding is not associated with differences in child cognitive outcomes at age 3, according to new results from the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study.

The study follows results from the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study, which found no evidence of cognitive harm in children who were exposed in utero to antiepileptic drugs. “[In the NEAD study] we followed our cohort to age 6 and found them to have actually an improvement in cognition by about 4 IQ points by the time they got to age 6,” Kimford J. Meador, MD, said during a presentation of the results of the MONEAD study at the 2022 annual meeting of the American Academy of Neurology.

Breastfeeding has health benefits for both mothers and children, including reduced risk of respiratory tract infections, atopic dermatitis, asthma, and diabetes in children, and reduced risk of diabetes, breast cancer, ovarian cancer, and postpartum depression in mothers. Despite those benefits, concerns about harms from exposure to antiepileptic drugs may prompt some women to avoid breastfeeding.

The results of NEAD and MONEAD should reassure patients, according to Dr. Meador, professor of neurology at Stanford (Calif.) University. “Given the known multiple benefits of breastfeeding … women with epilepsy should be encouraged to breastfeed,” he said.
 

A responsibility to ‘engage and educate’ patients

Jennifer Hopp, MD, who served as a discussant for the presentation, underscored the need for neurologists to address pregnancy with female patients of childbearing agents. “The issues may include fertility, peripartum management, and outcomes that really go through the lifespan to also include issues of menopause,” Dr. Hopp, associate professor of neurology at the University of Maryland, Baltimore, said during her presentation.

Dr. Hopp noted one study showing lower rates of breastfeeding among mothers with epilepsy. “Breastfeeding rates in women with epilepsy are strikingly lower than in women who do not have epilepsy,” said Dr. Hopp. Another study showed that women with epilepsy were less likely to sustain breastfeeding after 6 weeks.

Dr. Hopp implored neurologists to address this. “It’s our responsibility to engage and educate our patients. These data provide us messaging to our patients that the newer drugs do not adversely affect outcome independently of their other exposure, and really support well-informed choices in breastfeeding,” said Dr. Hopp.
 

Outdated attitudes still persist

Dr. Meador referred to the stigma that surrounds epilepsy, including some state laws that called for sterilization of women with epilepsy that lasted until the 1960s. One might think that such attitudes are gone, “but it’s still there,” said Dr. Meador, who recounted a story a colleague told him about a woman on antiseizure medication. In the hospital, the nurse told her not to breastfeed. The neurological consult told her not to breastfeed. She breastfed anyway. “Then they reported her for child neglect, and that was just a few years ago. So I think the message needs to be loud and clear that we encourage [women with epilepsy] to breastfeed because we have the known benefits, and now several studies showing clearly no adverse effects of breastfeeding while taking antiseizure medications,” said Dr. Meador.

MONEAD findings

The MONEAD study included women from 20 different sites, with 145 participating investigators. The researchers compared outcomes in 284 women with epilepsy and 87 healthy women. The maternal mean IQ was 98 among women with epilepsy (95% confidence interval [CI], 96-99), and 105 (95% CI, 102-107) among healthy women. Seventy-six percent of women with epilepsy breastfed, versus 89% of controls.

Among the study cohort, 79% of women with epilepsy were on monotherapy, and 21% were on polytherapy. Thirty-five percent received lamotrigine, 28% levetiracetam, 16% were on another monotherapy, 10% received a combination of lamotrigine and levetiracetam, and 11% received a different combination.

At age 3, there was no association between the verbal index score of the child and whether the mother had epilepsy or not (difference, 0.4; P = .770). The researchers did find associations with the mother’s IQ (0.3; P < .001), male versus female child sex (–4.9; P < .001), Hispanic or Latino ethnicity (vs. Non-Hispanic, –5.5; P < .001), mother without college degree (–7.0; P < .001), average Beck Anxiety Inventory score after birth (–0.4; P < .001), and weeks of gestational age at enrollment.

The researchers found no association between third trimester antiseizure medication blood levels and verbal index score after adjustment (–2.9; P = .149), with the exception of levetiracetam (–9.0; P = .033). “This is interesting (but) not to be overblown, because overall the children on levetiracetam did well. But it must be remembered that teratogens act in an exposure dependent manner, so we’re constantly in this balancing act of trying to make sure you get enough medication on board to stop the seizures and protect the mother and the child, and at the same time, not too much on board where we increase the risk of teratogenicity in the child,” said Dr. Meador.

The study was funded by the National Institutes of Health. Dr. Meador and Dr. Hopp have no relevant financial disclosures.

SEATTLE – Use of antiseizure medications while breastfeeding is not associated with differences in child cognitive outcomes at age 3, according to new results from the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study.

The study follows results from the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study, which found no evidence of cognitive harm in children who were exposed in utero to antiepileptic drugs. “[In the NEAD study] we followed our cohort to age 6 and found them to have actually an improvement in cognition by about 4 IQ points by the time they got to age 6,” Kimford J. Meador, MD, said during a presentation of the results of the MONEAD study at the 2022 annual meeting of the American Academy of Neurology.

Breastfeeding has health benefits for both mothers and children, including reduced risk of respiratory tract infections, atopic dermatitis, asthma, and diabetes in children, and reduced risk of diabetes, breast cancer, ovarian cancer, and postpartum depression in mothers. Despite those benefits, concerns about harms from exposure to antiepileptic drugs may prompt some women to avoid breastfeeding.

The results of NEAD and MONEAD should reassure patients, according to Dr. Meador, professor of neurology at Stanford (Calif.) University. “Given the known multiple benefits of breastfeeding … women with epilepsy should be encouraged to breastfeed,” he said.
 

A responsibility to ‘engage and educate’ patients

Jennifer Hopp, MD, who served as a discussant for the presentation, underscored the need for neurologists to address pregnancy with female patients of childbearing agents. “The issues may include fertility, peripartum management, and outcomes that really go through the lifespan to also include issues of menopause,” Dr. Hopp, associate professor of neurology at the University of Maryland, Baltimore, said during her presentation.

Dr. Hopp noted one study showing lower rates of breastfeeding among mothers with epilepsy. “Breastfeeding rates in women with epilepsy are strikingly lower than in women who do not have epilepsy,” said Dr. Hopp. Another study showed that women with epilepsy were less likely to sustain breastfeeding after 6 weeks.

Dr. Hopp implored neurologists to address this. “It’s our responsibility to engage and educate our patients. These data provide us messaging to our patients that the newer drugs do not adversely affect outcome independently of their other exposure, and really support well-informed choices in breastfeeding,” said Dr. Hopp.
 

Outdated attitudes still persist

Dr. Meador referred to the stigma that surrounds epilepsy, including some state laws that called for sterilization of women with epilepsy that lasted until the 1960s. One might think that such attitudes are gone, “but it’s still there,” said Dr. Meador, who recounted a story a colleague told him about a woman on antiseizure medication. In the hospital, the nurse told her not to breastfeed. The neurological consult told her not to breastfeed. She breastfed anyway. “Then they reported her for child neglect, and that was just a few years ago. So I think the message needs to be loud and clear that we encourage [women with epilepsy] to breastfeed because we have the known benefits, and now several studies showing clearly no adverse effects of breastfeeding while taking antiseizure medications,” said Dr. Meador.

MONEAD findings

The MONEAD study included women from 20 different sites, with 145 participating investigators. The researchers compared outcomes in 284 women with epilepsy and 87 healthy women. The maternal mean IQ was 98 among women with epilepsy (95% confidence interval [CI], 96-99), and 105 (95% CI, 102-107) among healthy women. Seventy-six percent of women with epilepsy breastfed, versus 89% of controls.

Among the study cohort, 79% of women with epilepsy were on monotherapy, and 21% were on polytherapy. Thirty-five percent received lamotrigine, 28% levetiracetam, 16% were on another monotherapy, 10% received a combination of lamotrigine and levetiracetam, and 11% received a different combination.

At age 3, there was no association between the verbal index score of the child and whether the mother had epilepsy or not (difference, 0.4; P = .770). The researchers did find associations with the mother’s IQ (0.3; P < .001), male versus female child sex (–4.9; P < .001), Hispanic or Latino ethnicity (vs. Non-Hispanic, –5.5; P < .001), mother without college degree (–7.0; P < .001), average Beck Anxiety Inventory score after birth (–0.4; P < .001), and weeks of gestational age at enrollment.

The researchers found no association between third trimester antiseizure medication blood levels and verbal index score after adjustment (–2.9; P = .149), with the exception of levetiracetam (–9.0; P = .033). “This is interesting (but) not to be overblown, because overall the children on levetiracetam did well. But it must be remembered that teratogens act in an exposure dependent manner, so we’re constantly in this balancing act of trying to make sure you get enough medication on board to stop the seizures and protect the mother and the child, and at the same time, not too much on board where we increase the risk of teratogenicity in the child,” said Dr. Meador.

The study was funded by the National Institutes of Health. Dr. Meador and Dr. Hopp have no relevant financial disclosures.

SEATTLE – Use of antiseizure medications while breastfeeding is not associated with differences in child cognitive outcomes at age 3, according to new results from the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study.

The study follows results from the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study, which found no evidence of cognitive harm in children who were exposed in utero to antiepileptic drugs. “[In the NEAD study] we followed our cohort to age 6 and found them to have actually an improvement in cognition by about 4 IQ points by the time they got to age 6,” Kimford J. Meador, MD, said during a presentation of the results of the MONEAD study at the 2022 annual meeting of the American Academy of Neurology.

Breastfeeding has health benefits for both mothers and children, including reduced risk of respiratory tract infections, atopic dermatitis, asthma, and diabetes in children, and reduced risk of diabetes, breast cancer, ovarian cancer, and postpartum depression in mothers. Despite those benefits, concerns about harms from exposure to antiepileptic drugs may prompt some women to avoid breastfeeding.

The results of NEAD and MONEAD should reassure patients, according to Dr. Meador, professor of neurology at Stanford (Calif.) University. “Given the known multiple benefits of breastfeeding … women with epilepsy should be encouraged to breastfeed,” he said.
 

A responsibility to ‘engage and educate’ patients

Jennifer Hopp, MD, who served as a discussant for the presentation, underscored the need for neurologists to address pregnancy with female patients of childbearing agents. “The issues may include fertility, peripartum management, and outcomes that really go through the lifespan to also include issues of menopause,” Dr. Hopp, associate professor of neurology at the University of Maryland, Baltimore, said during her presentation.

Dr. Hopp noted one study showing lower rates of breastfeeding among mothers with epilepsy. “Breastfeeding rates in women with epilepsy are strikingly lower than in women who do not have epilepsy,” said Dr. Hopp. Another study showed that women with epilepsy were less likely to sustain breastfeeding after 6 weeks.

Dr. Hopp implored neurologists to address this. “It’s our responsibility to engage and educate our patients. These data provide us messaging to our patients that the newer drugs do not adversely affect outcome independently of their other exposure, and really support well-informed choices in breastfeeding,” said Dr. Hopp.
 

Outdated attitudes still persist

Dr. Meador referred to the stigma that surrounds epilepsy, including some state laws that called for sterilization of women with epilepsy that lasted until the 1960s. One might think that such attitudes are gone, “but it’s still there,” said Dr. Meador, who recounted a story a colleague told him about a woman on antiseizure medication. In the hospital, the nurse told her not to breastfeed. The neurological consult told her not to breastfeed. She breastfed anyway. “Then they reported her for child neglect, and that was just a few years ago. So I think the message needs to be loud and clear that we encourage [women with epilepsy] to breastfeed because we have the known benefits, and now several studies showing clearly no adverse effects of breastfeeding while taking antiseizure medications,” said Dr. Meador.

MONEAD findings

The MONEAD study included women from 20 different sites, with 145 participating investigators. The researchers compared outcomes in 284 women with epilepsy and 87 healthy women. The maternal mean IQ was 98 among women with epilepsy (95% confidence interval [CI], 96-99), and 105 (95% CI, 102-107) among healthy women. Seventy-six percent of women with epilepsy breastfed, versus 89% of controls.

Among the study cohort, 79% of women with epilepsy were on monotherapy, and 21% were on polytherapy. Thirty-five percent received lamotrigine, 28% levetiracetam, 16% were on another monotherapy, 10% received a combination of lamotrigine and levetiracetam, and 11% received a different combination.

At age 3, there was no association between the verbal index score of the child and whether the mother had epilepsy or not (difference, 0.4; P = .770). The researchers did find associations with the mother’s IQ (0.3; P < .001), male versus female child sex (–4.9; P < .001), Hispanic or Latino ethnicity (vs. Non-Hispanic, –5.5; P < .001), mother without college degree (–7.0; P < .001), average Beck Anxiety Inventory score after birth (–0.4; P < .001), and weeks of gestational age at enrollment.

The researchers found no association between third trimester antiseizure medication blood levels and verbal index score after adjustment (–2.9; P = .149), with the exception of levetiracetam (–9.0; P = .033). “This is interesting (but) not to be overblown, because overall the children on levetiracetam did well. But it must be remembered that teratogens act in an exposure dependent manner, so we’re constantly in this balancing act of trying to make sure you get enough medication on board to stop the seizures and protect the mother and the child, and at the same time, not too much on board where we increase the risk of teratogenicity in the child,” said Dr. Meador.

The study was funded by the National Institutes of Health. Dr. Meador and Dr. Hopp have no relevant financial disclosures.

Anxiety and depression are common among individuals with inflammatory bowel disease (IBD) who are in remission, and the conditions are linked to unemployment and presenteeism, according to a prospective study.

Previous studies have found a heightened risk of anxiety and depression in IBD, as well as an association with poor treatment compliance and greater morbidity. Presenteeism, defined as reduced productivity due to a physical or mental condition, is increasingly recognized as an indirect economic cost of chronic conditions that may exact a higher cost than absenteeism.

Westend61/Getty Images

Anxiety and depression are common among individuals with inflammatory bowel disease (IBD) who are in remission, and the conditions are linked to unemployment and presenteeism, according to a prospective study.

Previous studies have found a heightened risk of anxiety and depression in IBD, as well as an association with poor treatment compliance and greater morbidity. Presenteeism, defined as reduced productivity due to a physical or mental condition, is increasingly recognized as an indirect economic cost of chronic conditions that may exact a higher cost than absenteeism.

Westend61/Getty Images

Anxiety and depression are common among individuals with inflammatory bowel disease (IBD) who are in remission, and the conditions are linked to unemployment and presenteeism, according to a prospective study.

Previous studies have found a heightened risk of anxiety and depression in IBD, as well as an association with poor treatment compliance and greater morbidity. Presenteeism, defined as reduced productivity due to a physical or mental condition, is increasingly recognized as an indirect economic cost of chronic conditions that may exact a higher cost than absenteeism.

Westend61/Getty Images

SEATTLE – The latest data from a phase 3 clinical trial shows that gene therapy can counter visual degeneration associated with Leber hereditary optic neuropathy (LHON). The therapy, delivered by intravitreal injection, uses an adeno-associated virus vector to deliver a corrected copy of the mutated ND4 mitochondrial gene.

LHON is a rare, maternally inherited mitochondrial mutation that can cause blindness, most commonly in young men, though it does not happen in all individuals with the mutation. The condition often starts with blindness in one eye, accompanied or followed shortly by blindness in the second eye. Researchers believe that the injected viral vector gets taken up retinal ganglion cells, where the mutated gene interferes with vision. Once synthesized, a mitochondria-targeting sequence facilitates transport of the protein to the mitochondria.

The study protocol called for injection of the therapy into one eye and a placebo into the other, using the patient as his or own placebo control. The results in the treated eye were encouraging, though modest. “This is not hitting it out of the ballpark. But for people whose vision is devastated by this disease, it certainly is a first step,” said Nancy J. Newman, MD, during a press conference held March 29 in advance of the 2022 annual meeting of the American Academy of Neurology.

Dr. Newman also noted a surprise finding: Visual improvement also occurred in the placebo-control eye. This was noted in previous studies, called RESCUE and REVERSE, and follow-up studies in monkeys found viral vector in the unaffected eye 3-6 months after an injection. “This would imply some kind of transport within retrograde up the opposite optic nerve after crossing in the chiasm to the eye, but this is going to take a fair bit of work to know exactly how that happens,” said Dr. Newman

Unfortunately, the phase 3 REFLECT study was designed before that process was understood. “This was not a case-control study by person, it was by eye. And that was a mistake, because it turns out there is a does appear to be second eye effects. We do not have naive controls here that did not receive any injection at all in any eye. That’s something that we will [do going] forward,” said Dr. Newman.

Despite the problem with placebo, the results were encouraging. “Those patients who had both eyes injected with the drug did better than in those who had one eye injected with drug and one eye injected with placebo, suggesting some sort of dose effect. There were no adverse events other than what we would expect from injecting [into] eyes. Those treated with the drug had more ocular inflammation, as would also be expected, but all were easily treated with topical medications,” said Dr. Newman.
 

What are the long-term effects?

Natalia Rost, MD, who chairs the AAN Science Committee, commented after the presentation: “We’re quite impressed with advances in gene therapy. The question is, are there early indications that this improvement in vision will have a lasting effect?”

Dr. Newman responded that ongoing data from earlier studies are also encouraging regarding the long-term effect of the treatment. At 4 years, there was a difference of 16.5 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters equivalent between treated patients and natural history controls (P < .01), “which [does] suggest that this effect is maintained,” said Dr. Newman, who is a professor of ophthalmology and neurology at Emory University, Atlanta.

Dr. Rost also wondered if it would be possible to capture patients earlier in their disease process, in the hopes of countering degeneration before it becomes severe enough to impact vision. Dr. Newman answered by noting another surprise from the research. Previous studies had shown that intervention while only a single eye is affected had little impact on spread of the condition to the second eye, “which was very disappointing,” said Dr. Newman. When they stratified patients by time since vision loss, they found that those who received the therapy 6 months or later after vision loss had better responses than those who were treated earlier.

The mechanism of this counter-intuitive finding remains uncertain, “but we do know that acutely in this disease when people are just starting to lose this vision, during the first couple of months, they get swelling of the axons from these retinal ganglion cells. Our hypothesis is that swelling may actually act as a barrier for the drug to get into the retinal ganglion cell bodies themselves and be transfected. So it turns out that earlier may not be better,” said Dr. Newman.

The study included patients at 13 sites worldwide; 48 were treated bilaterally and 50 treated unilaterally. Just under 80% were male, the mean age was 31.5 years, and the mean duration of vision loss was 8.30 months.

After 1.5 years, the improvement in best-corrected visual acuity between second-affected eyes was stronger in the treatment eye, equivalent to +3 ETDRS letters. The first-affected eye improved by 19 ETDRS letters, and the second-affected eye improved by 16 (P < .0001). Improvement in placebo eyes was +13 ETDRS letters (P < .0001).

Dr. Rost has served on a scientific advisory board or data monitoring board for Omniox. Dr. Newman has consulted for GenSight, Santhera/Chiesi, and Neurophoenix, and has received research support from GenSight and Santhera/Chiesi.

SEATTLE – The latest data from a phase 3 clinical trial shows that gene therapy can counter visual degeneration associated with Leber hereditary optic neuropathy (LHON). The therapy, delivered by intravitreal injection, uses an adeno-associated virus vector to deliver a corrected copy of the mutated ND4 mitochondrial gene.

LHON is a rare, maternally inherited mitochondrial mutation that can cause blindness, most commonly in young men, though it does not happen in all individuals with the mutation. The condition often starts with blindness in one eye, accompanied or followed shortly by blindness in the second eye. Researchers believe that the injected viral vector gets taken up retinal ganglion cells, where the mutated gene interferes with vision. Once synthesized, a mitochondria-targeting sequence facilitates transport of the protein to the mitochondria.

The study protocol called for injection of the therapy into one eye and a placebo into the other, using the patient as his or own placebo control. The results in the treated eye were encouraging, though modest. “This is not hitting it out of the ballpark. But for people whose vision is devastated by this disease, it certainly is a first step,” said Nancy J. Newman, MD, during a press conference held March 29 in advance of the 2022 annual meeting of the American Academy of Neurology.

Dr. Newman also noted a surprise finding: Visual improvement also occurred in the placebo-control eye. This was noted in previous studies, called RESCUE and REVERSE, and follow-up studies in monkeys found viral vector in the unaffected eye 3-6 months after an injection. “This would imply some kind of transport within retrograde up the opposite optic nerve after crossing in the chiasm to the eye, but this is going to take a fair bit of work to know exactly how that happens,” said Dr. Newman

Unfortunately, the phase 3 REFLECT study was designed before that process was understood. “This was not a case-control study by person, it was by eye. And that was a mistake, because it turns out there is a does appear to be second eye effects. We do not have naive controls here that did not receive any injection at all in any eye. That’s something that we will [do going] forward,” said Dr. Newman.

Despite the problem with placebo, the results were encouraging. “Those patients who had both eyes injected with the drug did better than in those who had one eye injected with drug and one eye injected with placebo, suggesting some sort of dose effect. There were no adverse events other than what we would expect from injecting [into] eyes. Those treated with the drug had more ocular inflammation, as would also be expected, but all were easily treated with topical medications,” said Dr. Newman.
 

What are the long-term effects?

Natalia Rost, MD, who chairs the AAN Science Committee, commented after the presentation: “We’re quite impressed with advances in gene therapy. The question is, are there early indications that this improvement in vision will have a lasting effect?”

Dr. Newman responded that ongoing data from earlier studies are also encouraging regarding the long-term effect of the treatment. At 4 years, there was a difference of 16.5 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters equivalent between treated patients and natural history controls (P < .01), “which [does] suggest that this effect is maintained,” said Dr. Newman, who is a professor of ophthalmology and neurology at Emory University, Atlanta.

Dr. Rost also wondered if it would be possible to capture patients earlier in their disease process, in the hopes of countering degeneration before it becomes severe enough to impact vision. Dr. Newman answered by noting another surprise from the research. Previous studies had shown that intervention while only a single eye is affected had little impact on spread of the condition to the second eye, “which was very disappointing,” said Dr. Newman. When they stratified patients by time since vision loss, they found that those who received the therapy 6 months or later after vision loss had better responses than those who were treated earlier.

The mechanism of this counter-intuitive finding remains uncertain, “but we do know that acutely in this disease when people are just starting to lose this vision, during the first couple of months, they get swelling of the axons from these retinal ganglion cells. Our hypothesis is that swelling may actually act as a barrier for the drug to get into the retinal ganglion cell bodies themselves and be transfected. So it turns out that earlier may not be better,” said Dr. Newman.

The study included patients at 13 sites worldwide; 48 were treated bilaterally and 50 treated unilaterally. Just under 80% were male, the mean age was 31.5 years, and the mean duration of vision loss was 8.30 months.

After 1.5 years, the improvement in best-corrected visual acuity between second-affected eyes was stronger in the treatment eye, equivalent to +3 ETDRS letters. The first-affected eye improved by 19 ETDRS letters, and the second-affected eye improved by 16 (P < .0001). Improvement in placebo eyes was +13 ETDRS letters (P < .0001).

Dr. Rost has served on a scientific advisory board or data monitoring board for Omniox. Dr. Newman has consulted for GenSight, Santhera/Chiesi, and Neurophoenix, and has received research support from GenSight and Santhera/Chiesi.

SEATTLE – The latest data from a phase 3 clinical trial shows that gene therapy can counter visual degeneration associated with Leber hereditary optic neuropathy (LHON). The therapy, delivered by intravitreal injection, uses an adeno-associated virus vector to deliver a corrected copy of the mutated ND4 mitochondrial gene.

LHON is a rare, maternally inherited mitochondrial mutation that can cause blindness, most commonly in young men, though it does not happen in all individuals with the mutation. The condition often starts with blindness in one eye, accompanied or followed shortly by blindness in the second eye. Researchers believe that the injected viral vector gets taken up retinal ganglion cells, where the mutated gene interferes with vision. Once synthesized, a mitochondria-targeting sequence facilitates transport of the protein to the mitochondria.

The study protocol called for injection of the therapy into one eye and a placebo into the other, using the patient as his or own placebo control. The results in the treated eye were encouraging, though modest. “This is not hitting it out of the ballpark. But for people whose vision is devastated by this disease, it certainly is a first step,” said Nancy J. Newman, MD, during a press conference held March 29 in advance of the 2022 annual meeting of the American Academy of Neurology.

Dr. Newman also noted a surprise finding: Visual improvement also occurred in the placebo-control eye. This was noted in previous studies, called RESCUE and REVERSE, and follow-up studies in monkeys found viral vector in the unaffected eye 3-6 months after an injection. “This would imply some kind of transport within retrograde up the opposite optic nerve after crossing in the chiasm to the eye, but this is going to take a fair bit of work to know exactly how that happens,” said Dr. Newman

Unfortunately, the phase 3 REFLECT study was designed before that process was understood. “This was not a case-control study by person, it was by eye. And that was a mistake, because it turns out there is a does appear to be second eye effects. We do not have naive controls here that did not receive any injection at all in any eye. That’s something that we will [do going] forward,” said Dr. Newman.

Despite the problem with placebo, the results were encouraging. “Those patients who had both eyes injected with the drug did better than in those who had one eye injected with drug and one eye injected with placebo, suggesting some sort of dose effect. There were no adverse events other than what we would expect from injecting [into] eyes. Those treated with the drug had more ocular inflammation, as would also be expected, but all were easily treated with topical medications,” said Dr. Newman.
 

What are the long-term effects?

Natalia Rost, MD, who chairs the AAN Science Committee, commented after the presentation: “We’re quite impressed with advances in gene therapy. The question is, are there early indications that this improvement in vision will have a lasting effect?”

Dr. Newman responded that ongoing data from earlier studies are also encouraging regarding the long-term effect of the treatment. At 4 years, there was a difference of 16.5 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters equivalent between treated patients and natural history controls (P < .01), “which [does] suggest that this effect is maintained,” said Dr. Newman, who is a professor of ophthalmology and neurology at Emory University, Atlanta.

Dr. Rost also wondered if it would be possible to capture patients earlier in their disease process, in the hopes of countering degeneration before it becomes severe enough to impact vision. Dr. Newman answered by noting another surprise from the research. Previous studies had shown that intervention while only a single eye is affected had little impact on spread of the condition to the second eye, “which was very disappointing,” said Dr. Newman. When they stratified patients by time since vision loss, they found that those who received the therapy 6 months or later after vision loss had better responses than those who were treated earlier.

The mechanism of this counter-intuitive finding remains uncertain, “but we do know that acutely in this disease when people are just starting to lose this vision, during the first couple of months, they get swelling of the axons from these retinal ganglion cells. Our hypothesis is that swelling may actually act as a barrier for the drug to get into the retinal ganglion cell bodies themselves and be transfected. So it turns out that earlier may not be better,” said Dr. Newman.

The study included patients at 13 sites worldwide; 48 were treated bilaterally and 50 treated unilaterally. Just under 80% were male, the mean age was 31.5 years, and the mean duration of vision loss was 8.30 months.

After 1.5 years, the improvement in best-corrected visual acuity between second-affected eyes was stronger in the treatment eye, equivalent to +3 ETDRS letters. The first-affected eye improved by 19 ETDRS letters, and the second-affected eye improved by 16 (P < .0001). Improvement in placebo eyes was +13 ETDRS letters (P < .0001).

Dr. Rost has served on a scientific advisory board or data monitoring board for Omniox. Dr. Newman has consulted for GenSight, Santhera/Chiesi, and Neurophoenix, and has received research support from GenSight and Santhera/Chiesi.

Among patients with advanced renal cell cancer treated with a combination of immune checkpoint inhibitors (ICI) and vascular endothelial growth factor (VEGF) inhibitors, high baseline levels of troponin T appear to predict future vulnerability to cardiovascular side effects, according to a planned post hoc analysis of data from the phase III JAVELIN Renal 101 trial.

The therapeutic combination is effective against several solid tumors, but ICIs are associated with cardiovascular events, including myocarditis in about 1% of patients. Although rare, the condition has a 46% mortality and 80% of the time occurs within 6 weeks of the start of treatment. It is unknown whether combination with VEGF inhibitors could heighten that risk.

“One of the areas that has been uncertain in kidney cancer with these VEGF combos is, what are the potential cardiac toxicities? How intensive monitoring do we need? How do we predict which patients might be at risk for these relatively rare but potentially serious events? So I think the value of the study is that it is a large prospective study where these measurements and endpoints were prospectively defined,” said lead author Brian Rini, MD, chief of clinical trials at Vanderbilt-Ingram Cancer Center.

The study, published online March 3 in the Journal of Clinical Oncology, doesn’t create specific recommendations for handling patients, Dr. Rini said. He suggests that physicians should consider more intense monitoring of patients on the regimen, along with upfront consultation with cardiologists, as well as keeping other treatment regimens in mind. “It’s hard to go much beyond just sort of an alert that this patient may be at higher risk than a patient without [heightened troponin T levels],” Dr. Rini said.

He also noted the finding that LVEF decline (≥10-point reduction from baseline to a value below the lower limit of normal) didn’t predict major adverse cardiac events (MACE), suggesting that echocardiograms, which have been done routinely since VEGF-targeted therapy was introduced, may not have much value in the general patient population. “It’s not that there’s no risk, but doing a lot of ECHOs on every single patient is just not an efficient way, as opposed to doing it in a more targeted fashion to patients with the relevant history and/or who developed suggestive symptoms,” Dr. Rini said.

The JAVELIN study randomized 442 patients (median age, 62.0; 71.5% male) to intravenous avelumab (Bavencio, Merck/Pfizer, 10 mg/kg) every 2 weeks plus oral axitinib (Inlyta, Pfizer, 5 mg) twice per day, and 439 patients (median age, 61.0; 77.5% male) to oral sunitinib (Sutent, Pfizer, 50 mg) once per day for 4 weeks. MACE were more common in the avelumab/axitinib group (7.1% vs. 3.9%). Left ventricular ejection fraction (LVEF) decline occurred more often in the avelumab/axitinib arm (8.5% vs. 1.6%; P < .0001), but there was no correlation between MACE and LVEF decline in either arm.

Patients in the avelumab/axitinib group with baseline levels of troponin T above the upper limit of normal were more likely to experience a MACE (17.1% vs. 5.2%; relative risk, 3.31; P = .022), but there was no difference in the sunitinib arm.

The study was funded by Pfizer. Dr. Rini has consulted for and received research funding from Pfizer.

Among patients with advanced renal cell cancer treated with a combination of immune checkpoint inhibitors (ICI) and vascular endothelial growth factor (VEGF) inhibitors, high baseline levels of troponin T appear to predict future vulnerability to cardiovascular side effects, according to a planned post hoc analysis of data from the phase III JAVELIN Renal 101 trial.

The therapeutic combination is effective against several solid tumors, but ICIs are associated with cardiovascular events, including myocarditis in about 1% of patients. Although rare, the condition has a 46% mortality and 80% of the time occurs within 6 weeks of the start of treatment. It is unknown whether combination with VEGF inhibitors could heighten that risk.

“One of the areas that has been uncertain in kidney cancer with these VEGF combos is, what are the potential cardiac toxicities? How intensive monitoring do we need? How do we predict which patients might be at risk for these relatively rare but potentially serious events? So I think the value of the study is that it is a large prospective study where these measurements and endpoints were prospectively defined,” said lead author Brian Rini, MD, chief of clinical trials at Vanderbilt-Ingram Cancer Center.

The study, published online March 3 in the Journal of Clinical Oncology, doesn’t create specific recommendations for handling patients, Dr. Rini said. He suggests that physicians should consider more intense monitoring of patients on the regimen, along with upfront consultation with cardiologists, as well as keeping other treatment regimens in mind. “It’s hard to go much beyond just sort of an alert that this patient may be at higher risk than a patient without [heightened troponin T levels],” Dr. Rini said.

He also noted the finding that LVEF decline (≥10-point reduction from baseline to a value below the lower limit of normal) didn’t predict major adverse cardiac events (MACE), suggesting that echocardiograms, which have been done routinely since VEGF-targeted therapy was introduced, may not have much value in the general patient population. “It’s not that there’s no risk, but doing a lot of ECHOs on every single patient is just not an efficient way, as opposed to doing it in a more targeted fashion to patients with the relevant history and/or who developed suggestive symptoms,” Dr. Rini said.

The JAVELIN study randomized 442 patients (median age, 62.0; 71.5% male) to intravenous avelumab (Bavencio, Merck/Pfizer, 10 mg/kg) every 2 weeks plus oral axitinib (Inlyta, Pfizer, 5 mg) twice per day, and 439 patients (median age, 61.0; 77.5% male) to oral sunitinib (Sutent, Pfizer, 50 mg) once per day for 4 weeks. MACE were more common in the avelumab/axitinib group (7.1% vs. 3.9%). Left ventricular ejection fraction (LVEF) decline occurred more often in the avelumab/axitinib arm (8.5% vs. 1.6%; P < .0001), but there was no correlation between MACE and LVEF decline in either arm.

Patients in the avelumab/axitinib group with baseline levels of troponin T above the upper limit of normal were more likely to experience a MACE (17.1% vs. 5.2%; relative risk, 3.31; P = .022), but there was no difference in the sunitinib arm.

The study was funded by Pfizer. Dr. Rini has consulted for and received research funding from Pfizer.

Among patients with advanced renal cell cancer treated with a combination of immune checkpoint inhibitors (ICI) and vascular endothelial growth factor (VEGF) inhibitors, high baseline levels of troponin T appear to predict future vulnerability to cardiovascular side effects, according to a planned post hoc analysis of data from the phase III JAVELIN Renal 101 trial.

The therapeutic combination is effective against several solid tumors, but ICIs are associated with cardiovascular events, including myocarditis in about 1% of patients. Although rare, the condition has a 46% mortality and 80% of the time occurs within 6 weeks of the start of treatment. It is unknown whether combination with VEGF inhibitors could heighten that risk.

“One of the areas that has been uncertain in kidney cancer with these VEGF combos is, what are the potential cardiac toxicities? How intensive monitoring do we need? How do we predict which patients might be at risk for these relatively rare but potentially serious events? So I think the value of the study is that it is a large prospective study where these measurements and endpoints were prospectively defined,” said lead author Brian Rini, MD, chief of clinical trials at Vanderbilt-Ingram Cancer Center.

The study, published online March 3 in the Journal of Clinical Oncology, doesn’t create specific recommendations for handling patients, Dr. Rini said. He suggests that physicians should consider more intense monitoring of patients on the regimen, along with upfront consultation with cardiologists, as well as keeping other treatment regimens in mind. “It’s hard to go much beyond just sort of an alert that this patient may be at higher risk than a patient without [heightened troponin T levels],” Dr. Rini said.

He also noted the finding that LVEF decline (≥10-point reduction from baseline to a value below the lower limit of normal) didn’t predict major adverse cardiac events (MACE), suggesting that echocardiograms, which have been done routinely since VEGF-targeted therapy was introduced, may not have much value in the general patient population. “It’s not that there’s no risk, but doing a lot of ECHOs on every single patient is just not an efficient way, as opposed to doing it in a more targeted fashion to patients with the relevant history and/or who developed suggestive symptoms,” Dr. Rini said.

The JAVELIN study randomized 442 patients (median age, 62.0; 71.5% male) to intravenous avelumab (Bavencio, Merck/Pfizer, 10 mg/kg) every 2 weeks plus oral axitinib (Inlyta, Pfizer, 5 mg) twice per day, and 439 patients (median age, 61.0; 77.5% male) to oral sunitinib (Sutent, Pfizer, 50 mg) once per day for 4 weeks. MACE were more common in the avelumab/axitinib group (7.1% vs. 3.9%). Left ventricular ejection fraction (LVEF) decline occurred more often in the avelumab/axitinib arm (8.5% vs. 1.6%; P < .0001), but there was no correlation between MACE and LVEF decline in either arm.

Patients in the avelumab/axitinib group with baseline levels of troponin T above the upper limit of normal were more likely to experience a MACE (17.1% vs. 5.2%; relative risk, 3.31; P = .022), but there was no difference in the sunitinib arm.

The study was funded by Pfizer. Dr. Rini has consulted for and received research funding from Pfizer.

The College of American Pathologists (CAP) guidance outperforms the Royal College of Pathologists (RCPath) guidance in predicting recurrence and survival following resection of oral cavity squamous cell carcinoma (OCSCC), according to a retrospective study.

Treatment of OCSCC involves resection of the primary tumor, followed by neck dissection or postoperative radiotherapy when needed, but choice of treatment requires an accurate assessment of resection margins. Previous studies have failed to consistently show a correlation between margin status and clinical outcomes. Tumor size, depth of invasion, and other factors may explain inconsistent findings, but another possibility is the variability in how margin status is defined.

RCPath and CAP are among the most commonly used definitions. RCPath defines a positive margin as invasive tumor within 1 mm of the surgical margin, while CAP defines a positive margin as the presence of primary tumor or high-grade dysplasia at the margin itself. CAP recommends determination of a “final margin status” that also considers separately submitted extra tumor bed margins. Nevertheless, multiple studies have shown that reliance on the main tumor specimen outperformed the combined approach in predicting recurrence and survival.

In a study published online March 7 in Oral Oncology, researchers examined records from 300 patients (33.7% of whom were female) at South Infirmary Victoria University Hospital in Ireland between 2007 and 2020. The researchers found that 28.7% had margins determined by the RCPath definition and 16.7% according to the CAP definition. Forty-nine percent underwent extra tumor bed resections.

The mean follow-up period was 49 months, 64 months for surviving patients. Multivariate analyses accounting for other established prognosticators found that local recurrence was associated with CAP margins (odds ratio [OR], 1.86; 955 confidence interval [CI], 1.02-3.48) and T3/T4 classification (OR, 2.80; 95% CI, 1.53-5.13). CAP margins predicted disease-specific survival (OR, 2.28; 95% CI, 1.53-5.13) and narrowly missed significance in predicting overall survival (OR, 1.65; 95% CI, 0.99-2.75). RCPath margins were not predictive.

The researchers found a significant association between RCPath definition and metastatic nodal disease and extranodal extension, but there was no such relationship between these negative predictors and CAP and final margin status. “This finding may explain the superior independent prognostic ability of CAP margin status over RCPath in our cohort and is consistent with that of previous studies, which concluded that other histological risk factors are more important than margin status in predicting outcome,” the authors wrote.

Studies suggest that margins fewer than 1 mm remain a high-risk group, with worse survival outcomes than those of patients with 1- to 5-mm margins, even if the risk is lower than tumor at margins. “The optimum cut-off between low-risk and high-risk margins in OCSCC remains unresolved,” the authors wrote.

The study was retrospective and relied on data from a single center, and the patients included in the study may not be directly comparable to other OCSCC patients. The study was funded by the Head and Neck Oncology Fund, South Infirmary Victoria University Hospital.

The College of American Pathologists (CAP) guidance outperforms the Royal College of Pathologists (RCPath) guidance in predicting recurrence and survival following resection of oral cavity squamous cell carcinoma (OCSCC), according to a retrospective study.

Treatment of OCSCC involves resection of the primary tumor, followed by neck dissection or postoperative radiotherapy when needed, but choice of treatment requires an accurate assessment of resection margins. Previous studies have failed to consistently show a correlation between margin status and clinical outcomes. Tumor size, depth of invasion, and other factors may explain inconsistent findings, but another possibility is the variability in how margin status is defined.

RCPath and CAP are among the most commonly used definitions. RCPath defines a positive margin as invasive tumor within 1 mm of the surgical margin, while CAP defines a positive margin as the presence of primary tumor or high-grade dysplasia at the margin itself. CAP recommends determination of a “final margin status” that also considers separately submitted extra tumor bed margins. Nevertheless, multiple studies have shown that reliance on the main tumor specimen outperformed the combined approach in predicting recurrence and survival.

In a study published online March 7 in Oral Oncology, researchers examined records from 300 patients (33.7% of whom were female) at South Infirmary Victoria University Hospital in Ireland between 2007 and 2020. The researchers found that 28.7% had margins determined by the RCPath definition and 16.7% according to the CAP definition. Forty-nine percent underwent extra tumor bed resections.

The mean follow-up period was 49 months, 64 months for surviving patients. Multivariate analyses accounting for other established prognosticators found that local recurrence was associated with CAP margins (odds ratio [OR], 1.86; 955 confidence interval [CI], 1.02-3.48) and T3/T4 classification (OR, 2.80; 95% CI, 1.53-5.13). CAP margins predicted disease-specific survival (OR, 2.28; 95% CI, 1.53-5.13) and narrowly missed significance in predicting overall survival (OR, 1.65; 95% CI, 0.99-2.75). RCPath margins were not predictive.

The researchers found a significant association between RCPath definition and metastatic nodal disease and extranodal extension, but there was no such relationship between these negative predictors and CAP and final margin status. “This finding may explain the superior independent prognostic ability of CAP margin status over RCPath in our cohort and is consistent with that of previous studies, which concluded that other histological risk factors are more important than margin status in predicting outcome,” the authors wrote.

Studies suggest that margins fewer than 1 mm remain a high-risk group, with worse survival outcomes than those of patients with 1- to 5-mm margins, even if the risk is lower than tumor at margins. “The optimum cut-off between low-risk and high-risk margins in OCSCC remains unresolved,” the authors wrote.

The study was retrospective and relied on data from a single center, and the patients included in the study may not be directly comparable to other OCSCC patients. The study was funded by the Head and Neck Oncology Fund, South Infirmary Victoria University Hospital.

The College of American Pathologists (CAP) guidance outperforms the Royal College of Pathologists (RCPath) guidance in predicting recurrence and survival following resection of oral cavity squamous cell carcinoma (OCSCC), according to a retrospective study.

Treatment of OCSCC involves resection of the primary tumor, followed by neck dissection or postoperative radiotherapy when needed, but choice of treatment requires an accurate assessment of resection margins. Previous studies have failed to consistently show a correlation between margin status and clinical outcomes. Tumor size, depth of invasion, and other factors may explain inconsistent findings, but another possibility is the variability in how margin status is defined.

RCPath and CAP are among the most commonly used definitions. RCPath defines a positive margin as invasive tumor within 1 mm of the surgical margin, while CAP defines a positive margin as the presence of primary tumor or high-grade dysplasia at the margin itself. CAP recommends determination of a “final margin status” that also considers separately submitted extra tumor bed margins. Nevertheless, multiple studies have shown that reliance on the main tumor specimen outperformed the combined approach in predicting recurrence and survival.

In a study published online March 7 in Oral Oncology, researchers examined records from 300 patients (33.7% of whom were female) at South Infirmary Victoria University Hospital in Ireland between 2007 and 2020. The researchers found that 28.7% had margins determined by the RCPath definition and 16.7% according to the CAP definition. Forty-nine percent underwent extra tumor bed resections.

The mean follow-up period was 49 months, 64 months for surviving patients. Multivariate analyses accounting for other established prognosticators found that local recurrence was associated with CAP margins (odds ratio [OR], 1.86; 955 confidence interval [CI], 1.02-3.48) and T3/T4 classification (OR, 2.80; 95% CI, 1.53-5.13). CAP margins predicted disease-specific survival (OR, 2.28; 95% CI, 1.53-5.13) and narrowly missed significance in predicting overall survival (OR, 1.65; 95% CI, 0.99-2.75). RCPath margins were not predictive.

The researchers found a significant association between RCPath definition and metastatic nodal disease and extranodal extension, but there was no such relationship between these negative predictors and CAP and final margin status. “This finding may explain the superior independent prognostic ability of CAP margin status over RCPath in our cohort and is consistent with that of previous studies, which concluded that other histological risk factors are more important than margin status in predicting outcome,” the authors wrote.

Studies suggest that margins fewer than 1 mm remain a high-risk group, with worse survival outcomes than those of patients with 1- to 5-mm margins, even if the risk is lower than tumor at margins. “The optimum cut-off between low-risk and high-risk margins in OCSCC remains unresolved,” the authors wrote.

The study was retrospective and relied on data from a single center, and the patients included in the study may not be directly comparable to other OCSCC patients. The study was funded by the Head and Neck Oncology Fund, South Infirmary Victoria University Hospital.

Perioperative immunotherapy appears to be safe in the setting of resectable hepatocellular carcinoma (HCC), according to findings from an open-label phase 2 clinical trial published in The Lancet Gastroenterology and Hepatolgy.

The study compared the anti-PD1 antibody nivolumab (Opdivo, Bristol Myers Squibb) alone and nivolumab plus the anti-CTLA-4 antibody ipilimumab (Yervoy, Bristol Myers Squibb) among patients with resectable disease at a single center in Sweden. The treatments were found to be “safe and feasible in patients with resectable hepatocellular carcinoma,” wrote researchers who were led by Ahmed O. Kaseb, MD, a medical oncologist with MD Anderson Cancer Center, Houston.

The rate of 5-year tumor recurrence following HCC resection can be as high as 70%, and there are no approved neoadjuvant or adjuvant therapies.

Immune checkpoint therapy has not been well studied in early-stage HCC, but it is used in advanced HCC.

The combination of PDL1 blockade with atezolizumab and VEGF blockade with bevacizumab, is currently a first-line treatment for advanced HCC. “Checkpoint inhibitors targeting PD1 and PDL1 and CTLA4 are active, tolerable, and clinically beneficial against advanced HCC,” according to researchers writing in a Nature Reviews article published in April 2021.

There are other promising immunotherapies under study for HCC, such as additional checkpoint inhibitors, adoptive cell transfer, vaccination, and virotherapy.
 

Small study of 27 patients

The Lancet study included 27 patients (64 years mean age, 19 patients were male). Twenty-three percent of patients on nivolumab alone had a partial pathological response at week 6, while none in the combination group had a response. Among 20 patients who underwent surgery, 3 of 9 (33%) and 3 of 11 (27%) in the combination group experienced a major pathological response. Two patients in the nivolumab and three patients in the combination group achieved a complete pathological response.

Disease progression occurred in 7 of 12 patients who were evaluated in the nivolumab group, and 4 of 13 patients in the combination group. Estimated median time to disease progression in the nivolumab group was 9.4 months (95% confidence interval, 1.47 to not estimable) and 19.53 months (95% CI, 2.33 to not estimable) in the combination group. Two-year progression-free survival was estimated to be 42% (95% CI, 21%-81%) in the nivolumab group and 26% (95% CI, 8%-78%, no significant difference) in the combination group.

Among 20 patients who underwent surgery, 6 patients had experienced a major pathological response. None of the 6 patients had a recurrence after a median follow-up of 26.8 months, versus 7 recurrences among 14 patients without a pathological response (log-rank P = .049).

Seventy-seven percent of patients in the nivolumab group experienced at least one adverse event (23% grade 3-4), as did 86% in the combination group (43% grade 3-4, difference nonsignificant). No patients delayed or canceled surgery because of adverse events.

Patients who had a major pathological response on the combination treatment had higher levels of immune infiltration versus baseline values. Those who had complete pathological responses in the nivolumab group had high infiltration at baseline. Those results imply some optimism for further study. “These data suggest that, with the immune-priming ability of anti–CTLA-4 treatment, nivolumab plus ipilimumab was able to generate a major pathological response even in tumours that had low immune infiltration at baseline,” the authors wrote.

The study was limited by its open-label nature and small sample size, and it was conducted at a single center.

The study was funded by Bristol Myers Squibb and the National Institutes of Health. Dr. Kaseb reports consulting, advisory roles or stock ownership, or both with Bristol-Myers Squibb.
 

Perioperative immunotherapy appears to be safe in the setting of resectable hepatocellular carcinoma (HCC), according to findings from an open-label phase 2 clinical trial published in The Lancet Gastroenterology and Hepatolgy.

The study compared the anti-PD1 antibody nivolumab (Opdivo, Bristol Myers Squibb) alone and nivolumab plus the anti-CTLA-4 antibody ipilimumab (Yervoy, Bristol Myers Squibb) among patients with resectable disease at a single center in Sweden. The treatments were found to be “safe and feasible in patients with resectable hepatocellular carcinoma,” wrote researchers who were led by Ahmed O. Kaseb, MD, a medical oncologist with MD Anderson Cancer Center, Houston.

The rate of 5-year tumor recurrence following HCC resection can be as high as 70%, and there are no approved neoadjuvant or adjuvant therapies.

Immune checkpoint therapy has not been well studied in early-stage HCC, but it is used in advanced HCC.

The combination of PDL1 blockade with atezolizumab and VEGF blockade with bevacizumab, is currently a first-line treatment for advanced HCC. “Checkpoint inhibitors targeting PD1 and PDL1 and CTLA4 are active, tolerable, and clinically beneficial against advanced HCC,” according to researchers writing in a Nature Reviews article published in April 2021.

There are other promising immunotherapies under study for HCC, such as additional checkpoint inhibitors, adoptive cell transfer, vaccination, and virotherapy.
 

Small study of 27 patients

The Lancet study included 27 patients (64 years mean age, 19 patients were male). Twenty-three percent of patients on nivolumab alone had a partial pathological response at week 6, while none in the combination group had a response. Among 20 patients who underwent surgery, 3 of 9 (33%) and 3 of 11 (27%) in the combination group experienced a major pathological response. Two patients in the nivolumab and three patients in the combination group achieved a complete pathological response.

Disease progression occurred in 7 of 12 patients who were evaluated in the nivolumab group, and 4 of 13 patients in the combination group. Estimated median time to disease progression in the nivolumab group was 9.4 months (95% confidence interval, 1.47 to not estimable) and 19.53 months (95% CI, 2.33 to not estimable) in the combination group. Two-year progression-free survival was estimated to be 42% (95% CI, 21%-81%) in the nivolumab group and 26% (95% CI, 8%-78%, no significant difference) in the combination group.

Among 20 patients who underwent surgery, 6 patients had experienced a major pathological response. None of the 6 patients had a recurrence after a median follow-up of 26.8 months, versus 7 recurrences among 14 patients without a pathological response (log-rank P = .049).

Seventy-seven percent of patients in the nivolumab group experienced at least one adverse event (23% grade 3-4), as did 86% in the combination group (43% grade 3-4, difference nonsignificant). No patients delayed or canceled surgery because of adverse events.

Patients who had a major pathological response on the combination treatment had higher levels of immune infiltration versus baseline values. Those who had complete pathological responses in the nivolumab group had high infiltration at baseline. Those results imply some optimism for further study. “These data suggest that, with the immune-priming ability of anti–CTLA-4 treatment, nivolumab plus ipilimumab was able to generate a major pathological response even in tumours that had low immune infiltration at baseline,” the authors wrote.

The study was limited by its open-label nature and small sample size, and it was conducted at a single center.

The study was funded by Bristol Myers Squibb and the National Institutes of Health. Dr. Kaseb reports consulting, advisory roles or stock ownership, or both with Bristol-Myers Squibb.
 

Perioperative immunotherapy appears to be safe in the setting of resectable hepatocellular carcinoma (HCC), according to findings from an open-label phase 2 clinical trial published in The Lancet Gastroenterology and Hepatolgy.

The study compared the anti-PD1 antibody nivolumab (Opdivo, Bristol Myers Squibb) alone and nivolumab plus the anti-CTLA-4 antibody ipilimumab (Yervoy, Bristol Myers Squibb) among patients with resectable disease at a single center in Sweden. The treatments were found to be “safe and feasible in patients with resectable hepatocellular carcinoma,” wrote researchers who were led by Ahmed O. Kaseb, MD, a medical oncologist with MD Anderson Cancer Center, Houston.

The rate of 5-year tumor recurrence following HCC resection can be as high as 70%, and there are no approved neoadjuvant or adjuvant therapies.

Immune checkpoint therapy has not been well studied in early-stage HCC, but it is used in advanced HCC.

The combination of PDL1 blockade with atezolizumab and VEGF blockade with bevacizumab, is currently a first-line treatment for advanced HCC. “Checkpoint inhibitors targeting PD1 and PDL1 and CTLA4 are active, tolerable, and clinically beneficial against advanced HCC,” according to researchers writing in a Nature Reviews article published in April 2021.

There are other promising immunotherapies under study for HCC, such as additional checkpoint inhibitors, adoptive cell transfer, vaccination, and virotherapy.
 

Small study of 27 patients

The Lancet study included 27 patients (64 years mean age, 19 patients were male). Twenty-three percent of patients on nivolumab alone had a partial pathological response at week 6, while none in the combination group had a response. Among 20 patients who underwent surgery, 3 of 9 (33%) and 3 of 11 (27%) in the combination group experienced a major pathological response. Two patients in the nivolumab and three patients in the combination group achieved a complete pathological response.

Disease progression occurred in 7 of 12 patients who were evaluated in the nivolumab group, and 4 of 13 patients in the combination group. Estimated median time to disease progression in the nivolumab group was 9.4 months (95% confidence interval, 1.47 to not estimable) and 19.53 months (95% CI, 2.33 to not estimable) in the combination group. Two-year progression-free survival was estimated to be 42% (95% CI, 21%-81%) in the nivolumab group and 26% (95% CI, 8%-78%, no significant difference) in the combination group.

Among 20 patients who underwent surgery, 6 patients had experienced a major pathological response. None of the 6 patients had a recurrence after a median follow-up of 26.8 months, versus 7 recurrences among 14 patients without a pathological response (log-rank P = .049).

Seventy-seven percent of patients in the nivolumab group experienced at least one adverse event (23% grade 3-4), as did 86% in the combination group (43% grade 3-4, difference nonsignificant). No patients delayed or canceled surgery because of adverse events.

Patients who had a major pathological response on the combination treatment had higher levels of immune infiltration versus baseline values. Those who had complete pathological responses in the nivolumab group had high infiltration at baseline. Those results imply some optimism for further study. “These data suggest that, with the immune-priming ability of anti–CTLA-4 treatment, nivolumab plus ipilimumab was able to generate a major pathological response even in tumours that had low immune infiltration at baseline,” the authors wrote.

The study was limited by its open-label nature and small sample size, and it was conducted at a single center.

The study was funded by Bristol Myers Squibb and the National Institutes of Health. Dr. Kaseb reports consulting, advisory roles or stock ownership, or both with Bristol-Myers Squibb.
 

Younger, nonsmoking oral cancer patients have a higher risk of death than that of young smokers, and the outcomes may be related to immune deficiencies. The finding comes from a database of oral cavity squamous cell carcinoma (OSCC) patients treated between 1985 and 2015.

“Recent studies have shown an association between high neutrophil to lymphocyte ratio as a marker for poor outcome in several different cancers. This ratio is a surrogate marker for a patient’s immune function. A high ratio indicates an impaired immune function. This means that the ability for the immune system to identify and eradicate abnormal cells which have the potential to form cancer cells is impaired. We don’t know why this is occurring,” said Ian Ganly, MD, PhD, a head and neck surgeon with Memorial Sloan Kettering Cancer Center in New York.

Dr. Ganly is lead author of the new study, published online March 5 in Oral Oncology.

“Physicians should be aware these patients may have impaired immunity and may have a more aggressive presentation and clinical behavior. Such patients may require more comprehensive staging investigations for cancer and may require more comprehensive treatment. Following treatment these patients should also have a detailed and regular follow-up examination with appropriate imaging to detect early recurrence,” he said in an interview.

The research also suggests that immunotherapy may be effective in this group. “However, our findings are only preliminary and further research into this area is required before such therapy can be justified,” Dr. Ganly said.

The study comprised 2,073 patients overall (median age, 62; 43.5% female) and 100 younger nonsmoking patients (median age, 34; 56.0% female). After multivariate analysis, compared to young smokers, nonsmokers with OSCC had a greater risk of mortality (P = .0229), although they had a lower mortality risk than both smokers and nonsmokers over 40. After adjustments, young nonsmokers had a mortality resembling that of older patients, while mortality among young smokers was distinctly lower than that of older patients.

In a subset of 88 young nonsmoking patients, there was a higher neutrophil-to-lymphocyte ratio (median, 2.456) than that of similarly aged patients with thyroid cancer (median, 2.000; P = .0093) or salivary gland benign pathologies (median, 2.158; P = .0343).

The researchers are now studying the genomics of tumors found in smokers and nonsmokers and comparing them to tumors in older smokers and nonsmokers with OSCCs. They are performing a similar comparison of the immune environment of the tumors and patients’ immune system function. “For the genomics aspect I am looking to see if there are any unique alterations in the young nonsmokers that may explain the biology of these cancers. If so, there may be some alterations that can be targeted with new drugs. For the immune aspect, our goal is to see if there are any specific alterations in immune function unique to this population. Then it may be possible to deliver specific types of immunotherapy that focus in on these deficiencies,” said Dr. Ganly.

The study was funded by Fundación Alfonso Martín Escudero and the National Institutes of Health. Dr. Ganly has no relevant financial disclosures.

Younger, nonsmoking oral cancer patients have a higher risk of death than that of young smokers, and the outcomes may be related to immune deficiencies. The finding comes from a database of oral cavity squamous cell carcinoma (OSCC) patients treated between 1985 and 2015.

“Recent studies have shown an association between high neutrophil to lymphocyte ratio as a marker for poor outcome in several different cancers. This ratio is a surrogate marker for a patient’s immune function. A high ratio indicates an impaired immune function. This means that the ability for the immune system to identify and eradicate abnormal cells which have the potential to form cancer cells is impaired. We don’t know why this is occurring,” said Ian Ganly, MD, PhD, a head and neck surgeon with Memorial Sloan Kettering Cancer Center in New York.

Dr. Ganly is lead author of the new study, published online March 5 in Oral Oncology.

“Physicians should be aware these patients may have impaired immunity and may have a more aggressive presentation and clinical behavior. Such patients may require more comprehensive staging investigations for cancer and may require more comprehensive treatment. Following treatment these patients should also have a detailed and regular follow-up examination with appropriate imaging to detect early recurrence,” he said in an interview.

The research also suggests that immunotherapy may be effective in this group. “However, our findings are only preliminary and further research into this area is required before such therapy can be justified,” Dr. Ganly said.

The study comprised 2,073 patients overall (median age, 62; 43.5% female) and 100 younger nonsmoking patients (median age, 34; 56.0% female). After multivariate analysis, compared to young smokers, nonsmokers with OSCC had a greater risk of mortality (P = .0229), although they had a lower mortality risk than both smokers and nonsmokers over 40. After adjustments, young nonsmokers had a mortality resembling that of older patients, while mortality among young smokers was distinctly lower than that of older patients.

In a subset of 88 young nonsmoking patients, there was a higher neutrophil-to-lymphocyte ratio (median, 2.456) than that of similarly aged patients with thyroid cancer (median, 2.000; P = .0093) or salivary gland benign pathologies (median, 2.158; P = .0343).

The researchers are now studying the genomics of tumors found in smokers and nonsmokers and comparing them to tumors in older smokers and nonsmokers with OSCCs. They are performing a similar comparison of the immune environment of the tumors and patients’ immune system function. “For the genomics aspect I am looking to see if there are any unique alterations in the young nonsmokers that may explain the biology of these cancers. If so, there may be some alterations that can be targeted with new drugs. For the immune aspect, our goal is to see if there are any specific alterations in immune function unique to this population. Then it may be possible to deliver specific types of immunotherapy that focus in on these deficiencies,” said Dr. Ganly.

The study was funded by Fundación Alfonso Martín Escudero and the National Institutes of Health. Dr. Ganly has no relevant financial disclosures.

Younger, nonsmoking oral cancer patients have a higher risk of death than that of young smokers, and the outcomes may be related to immune deficiencies. The finding comes from a database of oral cavity squamous cell carcinoma (OSCC) patients treated between 1985 and 2015.

“Recent studies have shown an association between high neutrophil to lymphocyte ratio as a marker for poor outcome in several different cancers. This ratio is a surrogate marker for a patient’s immune function. A high ratio indicates an impaired immune function. This means that the ability for the immune system to identify and eradicate abnormal cells which have the potential to form cancer cells is impaired. We don’t know why this is occurring,” said Ian Ganly, MD, PhD, a head and neck surgeon with Memorial Sloan Kettering Cancer Center in New York.

Dr. Ganly is lead author of the new study, published online March 5 in Oral Oncology.

“Physicians should be aware these patients may have impaired immunity and may have a more aggressive presentation and clinical behavior. Such patients may require more comprehensive staging investigations for cancer and may require more comprehensive treatment. Following treatment these patients should also have a detailed and regular follow-up examination with appropriate imaging to detect early recurrence,” he said in an interview.

The research also suggests that immunotherapy may be effective in this group. “However, our findings are only preliminary and further research into this area is required before such therapy can be justified,” Dr. Ganly said.

The study comprised 2,073 patients overall (median age, 62; 43.5% female) and 100 younger nonsmoking patients (median age, 34; 56.0% female). After multivariate analysis, compared to young smokers, nonsmokers with OSCC had a greater risk of mortality (P = .0229), although they had a lower mortality risk than both smokers and nonsmokers over 40. After adjustments, young nonsmokers had a mortality resembling that of older patients, while mortality among young smokers was distinctly lower than that of older patients.

In a subset of 88 young nonsmoking patients, there was a higher neutrophil-to-lymphocyte ratio (median, 2.456) than that of similarly aged patients with thyroid cancer (median, 2.000; P = .0093) or salivary gland benign pathologies (median, 2.158; P = .0343).

The researchers are now studying the genomics of tumors found in smokers and nonsmokers and comparing them to tumors in older smokers and nonsmokers with OSCCs. They are performing a similar comparison of the immune environment of the tumors and patients’ immune system function. “For the genomics aspect I am looking to see if there are any unique alterations in the young nonsmokers that may explain the biology of these cancers. If so, there may be some alterations that can be targeted with new drugs. For the immune aspect, our goal is to see if there are any specific alterations in immune function unique to this population. Then it may be possible to deliver specific types of immunotherapy that focus in on these deficiencies,” said Dr. Ganly.

The study was funded by Fundación Alfonso Martín Escudero and the National Institutes of Health. Dr. Ganly has no relevant financial disclosures.

Premenopausal women with a family history of breast cancer have a greater volume of breast density observed during mammography, according to a new study of two retrospective cohorts published online Feb. 17 in JAMA Network Open. The findings suggest that breast density measured during mammography may have a genetic component, and suggest the importance of initiating early mammography in premenopausal women with a family history of breast cancer.

“We know that mammographic breast density is a very strong risk factor for breast cancer, probably one of the strongest risk factors, and it’s also a surrogate marker for breast cancer development, especially in premenopausal women. We also know that family history of breast cancer is a strong risk factor for breast cancer as well. Surprisingly, we have very limited information on how these risk factors are related to each other. There have been only two studies that have been done in this field in premenopausal women, and the studies are conflicting. So, we felt that we need to really understand how these two factors are related to each other and whether that would have an impact on modifying or refining mammographic screening in high-risk women,” Adetunji T. Toriola, MD, PhD, MPH, said in an interview. Dr. Toriola is professor of surgery at Washington University, St. Louis.

Previous research identified risk factors for dense breast tissue. A genome-wide association study found 31 genetic loci associated with dense breast tissue, and 17 had a known association with breast cancer risk.

In the JAMA Network Open study, the researchers included data from women who were treated at Washington University’s Joanne Knight Breast Health Center and Siteman Cancer Center. The discovery group included 375 premenopausal women who received annual mammography screening in 2016 and had dense volume and non-dense volume measured during each screen. The validation set drew from 14,040 premenopausal women seen at the centers between 2010 and 2015.

In the discovery group, women with a family history of breast cancer had greater volumetric percent density (odds ratio [OR], 1.25; P < .001). The validation set produced a similar result (OR, 1.30; 95% confidence interval, 1.17-1.45). Subanalyses revealed similar associations in non-Hispanic White and Black or African American women.

The current study included a higher percentage of women with a family history of breast cancer than previous studies, and also controlled for more variables. This may have removed confounding variables that could have affected previous studies.

“It reinforces the need to start mammogram screening early in women who have a family history of breast cancer,” Dr. Toriola said.

The study had some limitations, including a higher percentage of women with a family history of breast cancer than the National Health Interview Survey (23.2% and 15.3%, versus 8.4%), explained by the fact that women with a family history of breast cancer are more likely to seek out screening. The average age of women was on average 47 years, making them closer to perimenopausal than premenopausal.

The study was funded by the National Institutes of Health.

Premenopausal women with a family history of breast cancer have a greater volume of breast density observed during mammography, according to a new study of two retrospective cohorts published online Feb. 17 in JAMA Network Open. The findings suggest that breast density measured during mammography may have a genetic component, and suggest the importance of initiating early mammography in premenopausal women with a family history of breast cancer.

“We know that mammographic breast density is a very strong risk factor for breast cancer, probably one of the strongest risk factors, and it’s also a surrogate marker for breast cancer development, especially in premenopausal women. We also know that family history of breast cancer is a strong risk factor for breast cancer as well. Surprisingly, we have very limited information on how these risk factors are related to each other. There have been only two studies that have been done in this field in premenopausal women, and the studies are conflicting. So, we felt that we need to really understand how these two factors are related to each other and whether that would have an impact on modifying or refining mammographic screening in high-risk women,” Adetunji T. Toriola, MD, PhD, MPH, said in an interview. Dr. Toriola is professor of surgery at Washington University, St. Louis.

Previous research identified risk factors for dense breast tissue. A genome-wide association study found 31 genetic loci associated with dense breast tissue, and 17 had a known association with breast cancer risk.

In the JAMA Network Open study, the researchers included data from women who were treated at Washington University’s Joanne Knight Breast Health Center and Siteman Cancer Center. The discovery group included 375 premenopausal women who received annual mammography screening in 2016 and had dense volume and non-dense volume measured during each screen. The validation set drew from 14,040 premenopausal women seen at the centers between 2010 and 2015.

In the discovery group, women with a family history of breast cancer had greater volumetric percent density (odds ratio [OR], 1.25; P < .001). The validation set produced a similar result (OR, 1.30; 95% confidence interval, 1.17-1.45). Subanalyses revealed similar associations in non-Hispanic White and Black or African American women.

The current study included a higher percentage of women with a family history of breast cancer than previous studies, and also controlled for more variables. This may have removed confounding variables that could have affected previous studies.

“It reinforces the need to start mammogram screening early in women who have a family history of breast cancer,” Dr. Toriola said.

The study had some limitations, including a higher percentage of women with a family history of breast cancer than the National Health Interview Survey (23.2% and 15.3%, versus 8.4%), explained by the fact that women with a family history of breast cancer are more likely to seek out screening. The average age of women was on average 47 years, making them closer to perimenopausal than premenopausal.

The study was funded by the National Institutes of Health.

Premenopausal women with a family history of breast cancer have a greater volume of breast density observed during mammography, according to a new study of two retrospective cohorts published online Feb. 17 in JAMA Network Open. The findings suggest that breast density measured during mammography may have a genetic component, and suggest the importance of initiating early mammography in premenopausal women with a family history of breast cancer.

“We know that mammographic breast density is a very strong risk factor for breast cancer, probably one of the strongest risk factors, and it’s also a surrogate marker for breast cancer development, especially in premenopausal women. We also know that family history of breast cancer is a strong risk factor for breast cancer as well. Surprisingly, we have very limited information on how these risk factors are related to each other. There have been only two studies that have been done in this field in premenopausal women, and the studies are conflicting. So, we felt that we need to really understand how these two factors are related to each other and whether that would have an impact on modifying or refining mammographic screening in high-risk women,” Adetunji T. Toriola, MD, PhD, MPH, said in an interview. Dr. Toriola is professor of surgery at Washington University, St. Louis.

Previous research identified risk factors for dense breast tissue. A genome-wide association study found 31 genetic loci associated with dense breast tissue, and 17 had a known association with breast cancer risk.

In the JAMA Network Open study, the researchers included data from women who were treated at Washington University’s Joanne Knight Breast Health Center and Siteman Cancer Center. The discovery group included 375 premenopausal women who received annual mammography screening in 2016 and had dense volume and non-dense volume measured during each screen. The validation set drew from 14,040 premenopausal women seen at the centers between 2010 and 2015.

In the discovery group, women with a family history of breast cancer had greater volumetric percent density (odds ratio [OR], 1.25; P < .001). The validation set produced a similar result (OR, 1.30; 95% confidence interval, 1.17-1.45). Subanalyses revealed similar associations in non-Hispanic White and Black or African American women.

The current study included a higher percentage of women with a family history of breast cancer than previous studies, and also controlled for more variables. This may have removed confounding variables that could have affected previous studies.

“It reinforces the need to start mammogram screening early in women who have a family history of breast cancer,” Dr. Toriola said.

The study had some limitations, including a higher percentage of women with a family history of breast cancer than the National Health Interview Survey (23.2% and 15.3%, versus 8.4%), explained by the fact that women with a family history of breast cancer are more likely to seek out screening. The average age of women was on average 47 years, making them closer to perimenopausal than premenopausal.

The study was funded by the National Institutes of Health.

For patients with psoriatic arthritis (PsA) whose condition doesn’t respond adequately to methotrexate, addition of the tumor necrosis factor (TNF) inhibitor adalimumab increased the likelihood of achieving minimum disease activity (MDA), compared with escalation of MTX dose, according to results from a phase 4, open-label study.

The new study is one of only a few to compare treatment protocols in a field that has seen new therapeutic options become available in recent years. That lack of evidence can leave patients and physicians uncertain about the next step if the initial results of treatment are disappointing.

“There are some gaps in our database and our understanding of psoriatic arthritis, compared to rheumatoid arthritis, where we have had many more studies over the years,” Arthur Kavanaugh, MD, told this news organization when asked to comment on the study.

The trial provides one answer, at least. “There was a clear-cut signal that it made more sense to add adalimumab at that early juncture where a person is not quite doing well enough on methotrexate to satisfy our goal of getting the patient to low disease activity. It gives us as clinicians some ammunition to speak to our insurance formulary people on this side of the Atlantic, or [for] people in the U.K. to go to their local regulatory board that approves medicines and be able to show them some actual practically derived evidence about this very common question that comes up in practice,” senior and corresponding author Philip Mease, MD, said in an interview. The study was published online in The Lancet Rheumatology.

“When a clinician and patient are making the decision to move on from methotrexate monotherapy, either because of lack of efficacy or safety issues, tolerability issues, it makes most sense to add on a biologic medication such as a TNF inhibitor at that juncture, rather than intensifying methotrexate therapy,” said Dr. Mease, who is director of rheumatology research at Swedish Medical Center/Providence St. Joseph Health and a clinical professor at the University of Washington, both in Seattle.

Physicians may be tempted to bump up the dose for patients who can tolerate MTX and who may be showing some improvement, but the new study should prompt a different strategy if MDA isn’t achieved, according to Oliver FitzGerald, MD, a professor at the Conway Institute for Biomolecular Research at University College Dublin, who was asked to comment on the study. “This study clearly shows that the early addition of adalimumab is the better choice, and it would change practice. That being said, there are clearly some patients who do respond sufficiently to increasing methotrexate, and it would be useful to be able to predict which patients might do that.” He added that the study focused on adalimumab and that the results might not apply to other biologics.

The study should encourage use of a quantitative treat-to-target measure like MDA, which is a composite measure of patient perspectives, Dr. Mease said. The American College of Rheumatology and National Psoriasis Foundation and Group for Research and Assessment of Psoriasis and Psoriatic Arthritis have recommended the use of MDA as a treat-to-target measure for PsA. The ACR and NPF recommend TNF inhibitors as first-line treatment, and GRAPPA includes it as a first-line option, whereas the European Alliance of Associations for Rheumatology recommends MTX only in the first line.

The study also suggests that there is value to using adalimumab on a weekly basis if an every-other-week schedule doesn’t produce the desired results. This strategy hasn’t been examined in PsA or even RA, according to Dr. Kavanaugh, who is a professor of medicine at the University of California, San Diego. “It did look like raising the dose might be an option for patients who are on every other week and are not doing quite as well as we would have hoped.”

The CONTROL study was a phase 4, two-part, open-label study. It included 245 patients in 14 countries who did not have MDA with MTX. In the first part of the study, patients were randomly assigned to receive weekly 15 mg MTX along with 40 mg adalimumab every other week, or escalation of MTX dose to 20-25 mg/week. MTX could be administered orally or intravenously. After 16 weeks (part 1), for patients who achieved MDA, current therapy was maintained or modified; for patients who did not achieve MDA, therapy was escalated over the following 16 weeks by giving adalimumab every week in the combination group or by adding adalimumab every other week in the MTX escalation arm.

Overall, 95% of the MTX plus adalimumab group completed part 1, as did 90% of the MTX escalation group. A total of 41% of the adalimumab group achieved MDA at 16 weeks versus 13% of the MTX group (P < .0001). The result held after accounting for sex and the interaction between sex and treatment (odds ratio, 4.6; 95% confidence interval, 2.4-8.9).

Among patients who achieved MDA at 16 weeks, 80% in the adalimumab group continued to have MDA at 32 weeks even after MTX had been withdrawn. Of those in the MTX escalation group, 67% continued to have MDA at 32 weeks with continued escalation of MTX.

Of the patients in the MTX escalation group who did not respond, 55% reached MDA following introduction of adalimumab every other week. Of those who did not respond to adalimumab, 30% reached MDA after switching to weekly adalimumab doses.

The study was open label, and patients who received adalimumab may have expected some improvement; that could have skewed the findings, Dr. Kavanaugh said. “I think that’s an important consideration as we interpret the data. The people who got the MTX arm probably had less of an expectation that they were going to do much better than those who switched to the adalimumab, as did the doctors taking care of them.”

The CONTROL study was funded by AbbVie. Dr. Mease has received research grants, consulted for, or received speaker honoraria from AbbVie, Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Galapagos, Gilead, Janssen, Lilly, Novartis, Pfizer, Sun Pharma, and UCB. Dr. FitzGerald has received grant support and honoraria from AbbVie. Dr. Kavanaugh has received research support from or consulted for AbbVie, Janssen, Pfizer, Lilly, Novartis, and UCB.

A version of this article first appeared on Medscape.com.

For patients with psoriatic arthritis (PsA) whose condition doesn’t respond adequately to methotrexate, addition of the tumor necrosis factor (TNF) inhibitor adalimumab increased the likelihood of achieving minimum disease activity (MDA), compared with escalation of MTX dose, according to results from a phase 4, open-label study.

The new study is one of only a few to compare treatment protocols in a field that has seen new therapeutic options become available in recent years. That lack of evidence can leave patients and physicians uncertain about the next step if the initial results of treatment are disappointing.

“There are some gaps in our database and our understanding of psoriatic arthritis, compared to rheumatoid arthritis, where we have had many more studies over the years,” Arthur Kavanaugh, MD, told this news organization when asked to comment on the study.

The trial provides one answer, at least. “There was a clear-cut signal that it made more sense to add adalimumab at that early juncture where a person is not quite doing well enough on methotrexate to satisfy our goal of getting the patient to low disease activity. It gives us as clinicians some ammunition to speak to our insurance formulary people on this side of the Atlantic, or [for] people in the U.K. to go to their local regulatory board that approves medicines and be able to show them some actual practically derived evidence about this very common question that comes up in practice,” senior and corresponding author Philip Mease, MD, said in an interview. The study was published online in The Lancet Rheumatology.

“When a clinician and patient are making the decision to move on from methotrexate monotherapy, either because of lack of efficacy or safety issues, tolerability issues, it makes most sense to add on a biologic medication such as a TNF inhibitor at that juncture, rather than intensifying methotrexate therapy,” said Dr. Mease, who is director of rheumatology research at Swedish Medical Center/Providence St. Joseph Health and a clinical professor at the University of Washington, both in Seattle.

Physicians may be tempted to bump up the dose for patients who can tolerate MTX and who may be showing some improvement, but the new study should prompt a different strategy if MDA isn’t achieved, according to Oliver FitzGerald, MD, a professor at the Conway Institute for Biomolecular Research at University College Dublin, who was asked to comment on the study. “This study clearly shows that the early addition of adalimumab is the better choice, and it would change practice. That being said, there are clearly some patients who do respond sufficiently to increasing methotrexate, and it would be useful to be able to predict which patients might do that.” He added that the study focused on adalimumab and that the results might not apply to other biologics.

The study should encourage use of a quantitative treat-to-target measure like MDA, which is a composite measure of patient perspectives, Dr. Mease said. The American College of Rheumatology and National Psoriasis Foundation and Group for Research and Assessment of Psoriasis and Psoriatic Arthritis have recommended the use of MDA as a treat-to-target measure for PsA. The ACR and NPF recommend TNF inhibitors as first-line treatment, and GRAPPA includes it as a first-line option, whereas the European Alliance of Associations for Rheumatology recommends MTX only in the first line.

The study also suggests that there is value to using adalimumab on a weekly basis if an every-other-week schedule doesn’t produce the desired results. This strategy hasn’t been examined in PsA or even RA, according to Dr. Kavanaugh, who is a professor of medicine at the University of California, San Diego. “It did look like raising the dose might be an option for patients who are on every other week and are not doing quite as well as we would have hoped.”

The CONTROL study was a phase 4, two-part, open-label study. It included 245 patients in 14 countries who did not have MDA with MTX. In the first part of the study, patients were randomly assigned to receive weekly 15 mg MTX along with 40 mg adalimumab every other week, or escalation of MTX dose to 20-25 mg/week. MTX could be administered orally or intravenously. After 16 weeks (part 1), for patients who achieved MDA, current therapy was maintained or modified; for patients who did not achieve MDA, therapy was escalated over the following 16 weeks by giving adalimumab every week in the combination group or by adding adalimumab every other week in the MTX escalation arm.

Overall, 95% of the MTX plus adalimumab group completed part 1, as did 90% of the MTX escalation group. A total of 41% of the adalimumab group achieved MDA at 16 weeks versus 13% of the MTX group (P < .0001). The result held after accounting for sex and the interaction between sex and treatment (odds ratio, 4.6; 95% confidence interval, 2.4-8.9).

Among patients who achieved MDA at 16 weeks, 80% in the adalimumab group continued to have MDA at 32 weeks even after MTX had been withdrawn. Of those in the MTX escalation group, 67% continued to have MDA at 32 weeks with continued escalation of MTX.

Of the patients in the MTX escalation group who did not respond, 55% reached MDA following introduction of adalimumab every other week. Of those who did not respond to adalimumab, 30% reached MDA after switching to weekly adalimumab doses.

The study was open label, and patients who received adalimumab may have expected some improvement; that could have skewed the findings, Dr. Kavanaugh said. “I think that’s an important consideration as we interpret the data. The people who got the MTX arm probably had less of an expectation that they were going to do much better than those who switched to the adalimumab, as did the doctors taking care of them.”

The CONTROL study was funded by AbbVie. Dr. Mease has received research grants, consulted for, or received speaker honoraria from AbbVie, Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Galapagos, Gilead, Janssen, Lilly, Novartis, Pfizer, Sun Pharma, and UCB. Dr. FitzGerald has received grant support and honoraria from AbbVie. Dr. Kavanaugh has received research support from or consulted for AbbVie, Janssen, Pfizer, Lilly, Novartis, and UCB.

A version of this article first appeared on Medscape.com.

For patients with psoriatic arthritis (PsA) whose condition doesn’t respond adequately to methotrexate, addition of the tumor necrosis factor (TNF) inhibitor adalimumab increased the likelihood of achieving minimum disease activity (MDA), compared with escalation of MTX dose, according to results from a phase 4, open-label study.

The new study is one of only a few to compare treatment protocols in a field that has seen new therapeutic options become available in recent years. That lack of evidence can leave patients and physicians uncertain about the next step if the initial results of treatment are disappointing.

“There are some gaps in our database and our understanding of psoriatic arthritis, compared to rheumatoid arthritis, where we have had many more studies over the years,” Arthur Kavanaugh, MD, told this news organization when asked to comment on the study.

The trial provides one answer, at least. “There was a clear-cut signal that it made more sense to add adalimumab at that early juncture where a person is not quite doing well enough on methotrexate to satisfy our goal of getting the patient to low disease activity. It gives us as clinicians some ammunition to speak to our insurance formulary people on this side of the Atlantic, or [for] people in the U.K. to go to their local regulatory board that approves medicines and be able to show them some actual practically derived evidence about this very common question that comes up in practice,” senior and corresponding author Philip Mease, MD, said in an interview. The study was published online in The Lancet Rheumatology.

“When a clinician and patient are making the decision to move on from methotrexate monotherapy, either because of lack of efficacy or safety issues, tolerability issues, it makes most sense to add on a biologic medication such as a TNF inhibitor at that juncture, rather than intensifying methotrexate therapy,” said Dr. Mease, who is director of rheumatology research at Swedish Medical Center/Providence St. Joseph Health and a clinical professor at the University of Washington, both in Seattle.

Physicians may be tempted to bump up the dose for patients who can tolerate MTX and who may be showing some improvement, but the new study should prompt a different strategy if MDA isn’t achieved, according to Oliver FitzGerald, MD, a professor at the Conway Institute for Biomolecular Research at University College Dublin, who was asked to comment on the study. “This study clearly shows that the early addition of adalimumab is the better choice, and it would change practice. That being said, there are clearly some patients who do respond sufficiently to increasing methotrexate, and it would be useful to be able to predict which patients might do that.” He added that the study focused on adalimumab and that the results might not apply to other biologics.

The study should encourage use of a quantitative treat-to-target measure like MDA, which is a composite measure of patient perspectives, Dr. Mease said. The American College of Rheumatology and National Psoriasis Foundation and Group for Research and Assessment of Psoriasis and Psoriatic Arthritis have recommended the use of MDA as a treat-to-target measure for PsA. The ACR and NPF recommend TNF inhibitors as first-line treatment, and GRAPPA includes it as a first-line option, whereas the European Alliance of Associations for Rheumatology recommends MTX only in the first line.

The study also suggests that there is value to using adalimumab on a weekly basis if an every-other-week schedule doesn’t produce the desired results. This strategy hasn’t been examined in PsA or even RA, according to Dr. Kavanaugh, who is a professor of medicine at the University of California, San Diego. “It did look like raising the dose might be an option for patients who are on every other week and are not doing quite as well as we would have hoped.”

The CONTROL study was a phase 4, two-part, open-label study. It included 245 patients in 14 countries who did not have MDA with MTX. In the first part of the study, patients were randomly assigned to receive weekly 15 mg MTX along with 40 mg adalimumab every other week, or escalation of MTX dose to 20-25 mg/week. MTX could be administered orally or intravenously. After 16 weeks (part 1), for patients who achieved MDA, current therapy was maintained or modified; for patients who did not achieve MDA, therapy was escalated over the following 16 weeks by giving adalimumab every week in the combination group or by adding adalimumab every other week in the MTX escalation arm.

Overall, 95% of the MTX plus adalimumab group completed part 1, as did 90% of the MTX escalation group. A total of 41% of the adalimumab group achieved MDA at 16 weeks versus 13% of the MTX group (P < .0001). The result held after accounting for sex and the interaction between sex and treatment (odds ratio, 4.6; 95% confidence interval, 2.4-8.9).

Among patients who achieved MDA at 16 weeks, 80% in the adalimumab group continued to have MDA at 32 weeks even after MTX had been withdrawn. Of those in the MTX escalation group, 67% continued to have MDA at 32 weeks with continued escalation of MTX.

Of the patients in the MTX escalation group who did not respond, 55% reached MDA following introduction of adalimumab every other week. Of those who did not respond to adalimumab, 30% reached MDA after switching to weekly adalimumab doses.

The study was open label, and patients who received adalimumab may have expected some improvement; that could have skewed the findings, Dr. Kavanaugh said. “I think that’s an important consideration as we interpret the data. The people who got the MTX arm probably had less of an expectation that they were going to do much better than those who switched to the adalimumab, as did the doctors taking care of them.”

The CONTROL study was funded by AbbVie. Dr. Mease has received research grants, consulted for, or received speaker honoraria from AbbVie, Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Galapagos, Gilead, Janssen, Lilly, Novartis, Pfizer, Sun Pharma, and UCB. Dr. FitzGerald has received grant support and honoraria from AbbVie. Dr. Kavanaugh has received research support from or consulted for AbbVie, Janssen, Pfizer, Lilly, Novartis, and UCB.

A version of this article first appeared on Medscape.com.