Cancer specialists have expressed disappointment at a decision by the National Institute for Health and Care Excellence not to recommend a targeted drug that can delay progression of a type of prostate cancer.

In draft guidance, NICE rejected olaparib (Lynparza, AstraZeneca) as a treatment option for hormone-relapsed metastatic prostate cancer with BRCA1/2 mutations.

The list price of the poly (ADP-ribose) polymerase inhibitor, at 37,491 pounds for an average cost of treatment, meant it was not cost effective to recommend for routine NHS use, the medicines regulator said.

The Institute of Cancer Research said the decision by NICE put patients in England and Wales at a disadvantage to those in Scotland where the regulator had approved olaparib for men with the same condition under a patient access scheme.

Kristian Helin, ICR chief executive, said: “I urge NICE and the manufacturer to come back to the table and try to find agreement on a way to make olaparib available at an agreeable price.”
 

Encouraging clinical evidence

Results from the PROfound trial, published in 2020 in the New England Journal of Medicine, suggested that progression-free survival for patients with prostate cancers who had faulty BRCA2, BRCA1, or ATM genes was significantly longer in the olaparib group than in a control group who received either enzalutamide or abiraterone.

Median survival in the Olaparib cohort was 7.4 months, compared with 3.6 months in the control group.

Retreatment with abiraterone or enzalutamide is not considered effective for men with this type of prostate cancer, and is not standard care in the NHS, NICE said.

Current treatment for metastatic hormone-relapsed prostate cancer is chemotherapy with docetaxel, cabazitaxel, or radium-223 dichloride.

NICE acknowledged that while an indirect comparison suggested that in men previously treated with docetaxel, olaparib increased survival, compared with cabazitaxel, there were no evidence directly comparing them.
 

Consultation period

Gillian Leng, CBE, NICE chief executive, said: “We know how important it is for people with this type of prostate cancer to have more treatment options that can help them live longer and enable them to maintain or improve their quality of life, as well as delay chemotherapy and its associated side effects.

“We’re therefore disappointed not to be able to recommend olaparib for use in this way. However, the company’s own economic model demonstrated that the drug does not offer enough benefit to justify the price it is asking.

“We’ll continue working with the company to try and address the issues highlighted by the committee.”

Johann De Bono, professor of experimental cancer medicine at the ICR, who leads the PROfound trial, said: “Olaparib is a precision drug that can extend life for men with some mutations in their tumors while sparing them the side effects of chemotherapy.

“I was delighted when olaparib was approved for NHS patients in Scotland earlier this year – and it’s disappointing that this decision means their counterparts in England and Wales will miss out on such a valuable new treatment option. It’s an example of the barriers that exist to making innovative drugs available at prices that the NHS can afford and is going to result in postcode prescribing across the U.K.”

The list price of olaparib is 2,317.50 pounds for a pack of 56 tablets covering 14 days of treatment. A confidential discount has been agreed by the manufacturer to make olaparib available to the NHS.

It is estimated that around 100 men would be eligible for treatment with olaparib if it was to be approved by NICE.

Consultation on the draft guidance closes on Jan. 31.

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

Cancer specialists have expressed disappointment at a decision by the National Institute for Health and Care Excellence not to recommend a targeted drug that can delay progression of a type of prostate cancer.

In draft guidance, NICE rejected olaparib (Lynparza, AstraZeneca) as a treatment option for hormone-relapsed metastatic prostate cancer with BRCA1/2 mutations.

The list price of the poly (ADP-ribose) polymerase inhibitor, at 37,491 pounds for an average cost of treatment, meant it was not cost effective to recommend for routine NHS use, the medicines regulator said.

The Institute of Cancer Research said the decision by NICE put patients in England and Wales at a disadvantage to those in Scotland where the regulator had approved olaparib for men with the same condition under a patient access scheme.

Kristian Helin, ICR chief executive, said: “I urge NICE and the manufacturer to come back to the table and try to find agreement on a way to make olaparib available at an agreeable price.”
 

Encouraging clinical evidence

Results from the PROfound trial, published in 2020 in the New England Journal of Medicine, suggested that progression-free survival for patients with prostate cancers who had faulty BRCA2, BRCA1, or ATM genes was significantly longer in the olaparib group than in a control group who received either enzalutamide or abiraterone.

Median survival in the Olaparib cohort was 7.4 months, compared with 3.6 months in the control group.

Retreatment with abiraterone or enzalutamide is not considered effective for men with this type of prostate cancer, and is not standard care in the NHS, NICE said.

Current treatment for metastatic hormone-relapsed prostate cancer is chemotherapy with docetaxel, cabazitaxel, or radium-223 dichloride.

NICE acknowledged that while an indirect comparison suggested that in men previously treated with docetaxel, olaparib increased survival, compared with cabazitaxel, there were no evidence directly comparing them.
 

Consultation period

Gillian Leng, CBE, NICE chief executive, said: “We know how important it is for people with this type of prostate cancer to have more treatment options that can help them live longer and enable them to maintain or improve their quality of life, as well as delay chemotherapy and its associated side effects.

“We’re therefore disappointed not to be able to recommend olaparib for use in this way. However, the company’s own economic model demonstrated that the drug does not offer enough benefit to justify the price it is asking.

“We’ll continue working with the company to try and address the issues highlighted by the committee.”

Johann De Bono, professor of experimental cancer medicine at the ICR, who leads the PROfound trial, said: “Olaparib is a precision drug that can extend life for men with some mutations in their tumors while sparing them the side effects of chemotherapy.

“I was delighted when olaparib was approved for NHS patients in Scotland earlier this year – and it’s disappointing that this decision means their counterparts in England and Wales will miss out on such a valuable new treatment option. It’s an example of the barriers that exist to making innovative drugs available at prices that the NHS can afford and is going to result in postcode prescribing across the U.K.”

The list price of olaparib is 2,317.50 pounds for a pack of 56 tablets covering 14 days of treatment. A confidential discount has been agreed by the manufacturer to make olaparib available to the NHS.

It is estimated that around 100 men would be eligible for treatment with olaparib if it was to be approved by NICE.

Consultation on the draft guidance closes on Jan. 31.

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

Cancer specialists have expressed disappointment at a decision by the National Institute for Health and Care Excellence not to recommend a targeted drug that can delay progression of a type of prostate cancer.

In draft guidance, NICE rejected olaparib (Lynparza, AstraZeneca) as a treatment option for hormone-relapsed metastatic prostate cancer with BRCA1/2 mutations.

The list price of the poly (ADP-ribose) polymerase inhibitor, at 37,491 pounds for an average cost of treatment, meant it was not cost effective to recommend for routine NHS use, the medicines regulator said.

The Institute of Cancer Research said the decision by NICE put patients in England and Wales at a disadvantage to those in Scotland where the regulator had approved olaparib for men with the same condition under a patient access scheme.

Kristian Helin, ICR chief executive, said: “I urge NICE and the manufacturer to come back to the table and try to find agreement on a way to make olaparib available at an agreeable price.”
 

Encouraging clinical evidence

Results from the PROfound trial, published in 2020 in the New England Journal of Medicine, suggested that progression-free survival for patients with prostate cancers who had faulty BRCA2, BRCA1, or ATM genes was significantly longer in the olaparib group than in a control group who received either enzalutamide or abiraterone.

Median survival in the Olaparib cohort was 7.4 months, compared with 3.6 months in the control group.

Retreatment with abiraterone or enzalutamide is not considered effective for men with this type of prostate cancer, and is not standard care in the NHS, NICE said.

Current treatment for metastatic hormone-relapsed prostate cancer is chemotherapy with docetaxel, cabazitaxel, or radium-223 dichloride.

NICE acknowledged that while an indirect comparison suggested that in men previously treated with docetaxel, olaparib increased survival, compared with cabazitaxel, there were no evidence directly comparing them.
 

Consultation period

Gillian Leng, CBE, NICE chief executive, said: “We know how important it is for people with this type of prostate cancer to have more treatment options that can help them live longer and enable them to maintain or improve their quality of life, as well as delay chemotherapy and its associated side effects.

“We’re therefore disappointed not to be able to recommend olaparib for use in this way. However, the company’s own economic model demonstrated that the drug does not offer enough benefit to justify the price it is asking.

“We’ll continue working with the company to try and address the issues highlighted by the committee.”

Johann De Bono, professor of experimental cancer medicine at the ICR, who leads the PROfound trial, said: “Olaparib is a precision drug that can extend life for men with some mutations in their tumors while sparing them the side effects of chemotherapy.

“I was delighted when olaparib was approved for NHS patients in Scotland earlier this year – and it’s disappointing that this decision means their counterparts in England and Wales will miss out on such a valuable new treatment option. It’s an example of the barriers that exist to making innovative drugs available at prices that the NHS can afford and is going to result in postcode prescribing across the U.K.”

The list price of olaparib is 2,317.50 pounds for a pack of 56 tablets covering 14 days of treatment. A confidential discount has been agreed by the manufacturer to make olaparib available to the NHS.

It is estimated that around 100 men would be eligible for treatment with olaparib if it was to be approved by NICE.

Consultation on the draft guidance closes on Jan. 31.

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

A shave biopsy (performed carefully to avoid caustic hemostatic agents irritating the conjunctiva) confirmed the diagnosis of a micronodular basal cell carcinoma (BCC).

BCC is a common tumor occurring on the eyelids and in the periocular region. Any new growing papule on the eyelids, history of focal bleeding, irritation, or focal loss of eyelashes should cause suspicion for BCC. Patients are often unaware of any symptoms when lesions begin, highlighting the importance of close inspection of the eyelids when skin or eye exams are performed. The differential diagnosis includes benign lesions such as hidrocystomas and nevi, as well as malignancies, including sebaceous carcinoma and squamous cell carcinoma.¹

Factors that come into play when exploring eyelid BCC treatment options include tumor removal, eyelid function, and appearance. The potential morbidity associated with tumor spread in the periorbital region highlights the importance of early detection of eyelid cancers. Mohs micrographic surgery (MMS) is a first choice for tumor removal of an eyelid BCC and offers a high cure rate with minimal tissue removal.

Removal of an eyelid BCC may be a multidisciplinary endeavor with MMS achieving a clear margin, and Ophthalmology or Oculoplastics following with repair and closure soon after. Patients who can’t tolerate surgery should consider vismodegib, a targeted chemotherapy, or radiotherapy.

The patient in this case opted for a single staged excision and repair with Oculoplastics and has had no recurrence. He subsequently underwent a revision procedure to improve ectropion.

‌

Text courtesy of Jonathan Karnes, MD, medical director, MDFMR Dermatology Services, Augusta, ME. Photos courtesy of Jonathan Karnes, MD (copyright retained).

A shave biopsy (performed carefully to avoid caustic hemostatic agents irritating the conjunctiva) confirmed the diagnosis of a micronodular basal cell carcinoma (BCC).

BCC is a common tumor occurring on the eyelids and in the periocular region. Any new growing papule on the eyelids, history of focal bleeding, irritation, or focal loss of eyelashes should cause suspicion for BCC. Patients are often unaware of any symptoms when lesions begin, highlighting the importance of close inspection of the eyelids when skin or eye exams are performed. The differential diagnosis includes benign lesions such as hidrocystomas and nevi, as well as malignancies, including sebaceous carcinoma and squamous cell carcinoma.¹

Factors that come into play when exploring eyelid BCC treatment options include tumor removal, eyelid function, and appearance. The potential morbidity associated with tumor spread in the periorbital region highlights the importance of early detection of eyelid cancers. Mohs micrographic surgery (MMS) is a first choice for tumor removal of an eyelid BCC and offers a high cure rate with minimal tissue removal.

Removal of an eyelid BCC may be a multidisciplinary endeavor with MMS achieving a clear margin, and Ophthalmology or Oculoplastics following with repair and closure soon after. Patients who can’t tolerate surgery should consider vismodegib, a targeted chemotherapy, or radiotherapy.

The patient in this case opted for a single staged excision and repair with Oculoplastics and has had no recurrence. He subsequently underwent a revision procedure to improve ectropion.

‌

Text courtesy of Jonathan Karnes, MD, medical director, MDFMR Dermatology Services, Augusta, ME. Photos courtesy of Jonathan Karnes, MD (copyright retained).

A shave biopsy (performed carefully to avoid caustic hemostatic agents irritating the conjunctiva) confirmed the diagnosis of a micronodular basal cell carcinoma (BCC).

BCC is a common tumor occurring on the eyelids and in the periocular region. Any new growing papule on the eyelids, history of focal bleeding, irritation, or focal loss of eyelashes should cause suspicion for BCC. Patients are often unaware of any symptoms when lesions begin, highlighting the importance of close inspection of the eyelids when skin or eye exams are performed. The differential diagnosis includes benign lesions such as hidrocystomas and nevi, as well as malignancies, including sebaceous carcinoma and squamous cell carcinoma.¹

Factors that come into play when exploring eyelid BCC treatment options include tumor removal, eyelid function, and appearance. The potential morbidity associated with tumor spread in the periorbital region highlights the importance of early detection of eyelid cancers. Mohs micrographic surgery (MMS) is a first choice for tumor removal of an eyelid BCC and offers a high cure rate with minimal tissue removal.

Removal of an eyelid BCC may be a multidisciplinary endeavor with MMS achieving a clear margin, and Ophthalmology or Oculoplastics following with repair and closure soon after. Patients who can’t tolerate surgery should consider vismodegib, a targeted chemotherapy, or radiotherapy.

The patient in this case opted for a single staged excision and repair with Oculoplastics and has had no recurrence. He subsequently underwent a revision procedure to improve ectropion.

‌

Text courtesy of Jonathan Karnes, MD, medical director, MDFMR Dermatology Services, Augusta, ME. Photos courtesy of Jonathan Karnes, MD (copyright retained).

I am a psychiatrist, which means I am a mental health professional, which means I work with people with mental illness. Sometimes people with mental health conditions who suffer from mental illness need to take a day off work – also called a mental health day – because they are too symptomatic to work, and sometimes people who don’t have a mental illness need to take a day off work, also called a mental health day, because they are feeling stressed.

Sometimes professional athletes don’t do things they agreed to do in their contracts because they realize that doing these things is very upsetting and will be detrimental to their mental health, or maybe they have a mental illness and doing these things will worsen their mental health condition, which is, in fact, a mental illness. Other times people with mental health conditions need to have pets travel with them because this mitigates the symptoms of their mental illness or perhaps it’s just good for their mental health. And finally, some people suffer from mental illnesses, or sometimes from learning problems, which are severe enough that a person with these conditions has a disability and needs special accommodations to function optimally in educational or occupational settings, or needs public financial support because their difficulties disable them to the point that they can’t work at all.

Is your head spinning yet? The point I am trying to make is that, as a profession, we have done an abysmal job of defining what we do, who we serve, and differentiating the fact that what someone with a psychiatric disorder needs to do to function or to alleviate emotional suffering may be entirely different from the things that everyone needs to do, regardless of whether they have a psychiatric disorder, to feel their emotional best.

The National Alliance on Mental Illness tells us that one in five Americans are suffering from a mental illness, while the Epidemiologic Catchment Area Program revealed that half of people will meet criteria for a mental illness at some point in their lives. We hear about “the mentally ill” constantly in the news – often in relation to mass shooters or homelessness – yet even psychiatrists might be pressed to define who exactly the “mentally ill” are. And how many of us could not somehow, at some time, find ourselves in 1 of the 157 disorders that DSM-5 lists – down from 365 disorders in the DSM-IV-TR?

Differentiating mental health from mental illness is just the beginning of our semantic confusion. As psychiatrists we treat major depression, and yet the illness “depression,” a syndromic constellation of symptoms, includes the key symptom of sadness. People often say they are “depressed” when they mean they are sad or demoralized, and yet, if their sadness persists in the absence of other symptoms, they may well want, or feel they “should” have medications, even in the absence of a disorder. And maybe those medications help them feel better, so that the presence or absence of a verified illness doesn’t really matter. But if the medications cause adverse reactions, then psychiatry might have done a better job by that person’s sadness. Melancholia, or perhaps any designation than “depression,” with its multiple meanings, might better serve our patients and our profession. This is only one example, as the number of people who tell me they have obsessive-compulsive disorder – or more often announce, “I’m OCD!” because they are well organized in a productive way is remarkable. And while I have treated only a few people who meet the criteria for narcissistic personality disorder, from general conversation it would seem that they are at every dinner table and by every water cooler.

Does it matter? A diagnostic lexicon can be so helpful when it guides treatment, provides a heterogeneous group of patients for research studies, and allows for an understanding of the etiology, course, and prognosis of a given condition. When someone is so depressed that they can’t get out of bed, or is so disorganized that they can’t perform their job and might cause a disturbance in their workplace, it is good to instruct them to take time off work and send them back well with a doctor’s note. But this is different from the person who doesn’t want to face a difficult situation, who simply doesn’t like their job or their boss, or who wants their pet declared an emotional support animal to avoid the fee the airlines charge to bring an animal on board if one does not have a psychiatric diagnosis. Sometimes these lines are blurry – if someone does not want to do something because it makes them anxious, does it matter how deep the pit in their stomach is, or if they are having full-blown panic attacks? When do we agree that their distress is reason to allow them to avoid responsibilities without repercussions versus a violation of their obligations and an infringement on others?

Diagnoses offer solace to some patients: There is a name for their suffering, available treatment, and often others with the same condition to look to for guidance and community. For others, a psychiatric diagnosis is a source of shame, a label they see as damaging to their character and sometimes to their careers – including in medicine – where we have been particularly unsympathetic to those who announce a psychiatric history.

In some cultures, the label itself decreases someone’s attractiveness as a potential marriage partner. We would all like to see the stigma of mental illness vanish, but we have a long way to go.

Psychiatric diagnoses move over time and with our politics and culture. This is good; we don’t hold on to what we learn to be untrue. But they may well add to issues of inequity. Those who can afford to pay for expensive educational assessments can request educational accommodations, including untimed standardized tests. This advantage may not be available to those without the resources to pay for these evaluations, and one might wonder why all comers can’t take untimed tests so as not to favor the privileged. Psychiatry has long been accused of diagnosing people of color with poor prognosis illnesses and women with conditions that imply emotional weakness.

While our diagnoses have clinical utility, it is unfortunate that they have come to be about reimbursement. A diagnosis needs to be assigned for insurers to pay for care, and so we create diagnostic categories to allow for treatment. Is this reasonable? Do we need to say that someone who is suffering after the death of a loved one has a mental illness in order to allow them to seek relief from their suffering? It leads us to believe that all suffering is about pathology, that we should expect pain-free emotional lives. Perhaps we need a diagnostic category of psychic pain, not otherwise specified, to allow for treatment for those who simply ache.

Mental illness is about interventions to alleviate the suffering of those with disorders. Mental health is about interventions that may benefit everyone, whether they suffer from a mental illness or not. Sleep, nutrition, exercise, sunlight, nature, entertainment and escape, yoga, meditation, vacations in beautiful places with loving people – these are things that potentially help us all whether we do or do not have an illness. With so much confusion about what it is we do, and about who “should” get help, who can get help, who might want help, and where they should go to seek help, perhaps it would be better if our lingo were more precise.

Dr. Miller is coauthor of “Committed: The Battle Over Involuntary Psychiatric Care” (Baltimore: Johns Hopkins University Press, 2016). The has a private practice and is assistant professor of psychiatry ad behavioral sciences at Johns Hopkins University, both in Baltimore. She has no disclosures.

I am a psychiatrist, which means I am a mental health professional, which means I work with people with mental illness. Sometimes people with mental health conditions who suffer from mental illness need to take a day off work – also called a mental health day – because they are too symptomatic to work, and sometimes people who don’t have a mental illness need to take a day off work, also called a mental health day, because they are feeling stressed.

Sometimes professional athletes don’t do things they agreed to do in their contracts because they realize that doing these things is very upsetting and will be detrimental to their mental health, or maybe they have a mental illness and doing these things will worsen their mental health condition, which is, in fact, a mental illness. Other times people with mental health conditions need to have pets travel with them because this mitigates the symptoms of their mental illness or perhaps it’s just good for their mental health. And finally, some people suffer from mental illnesses, or sometimes from learning problems, which are severe enough that a person with these conditions has a disability and needs special accommodations to function optimally in educational or occupational settings, or needs public financial support because their difficulties disable them to the point that they can’t work at all.

Is your head spinning yet? The point I am trying to make is that, as a profession, we have done an abysmal job of defining what we do, who we serve, and differentiating the fact that what someone with a psychiatric disorder needs to do to function or to alleviate emotional suffering may be entirely different from the things that everyone needs to do, regardless of whether they have a psychiatric disorder, to feel their emotional best.

The National Alliance on Mental Illness tells us that one in five Americans are suffering from a mental illness, while the Epidemiologic Catchment Area Program revealed that half of people will meet criteria for a mental illness at some point in their lives. We hear about “the mentally ill” constantly in the news – often in relation to mass shooters or homelessness – yet even psychiatrists might be pressed to define who exactly the “mentally ill” are. And how many of us could not somehow, at some time, find ourselves in 1 of the 157 disorders that DSM-5 lists – down from 365 disorders in the DSM-IV-TR?

Differentiating mental health from mental illness is just the beginning of our semantic confusion. As psychiatrists we treat major depression, and yet the illness “depression,” a syndromic constellation of symptoms, includes the key symptom of sadness. People often say they are “depressed” when they mean they are sad or demoralized, and yet, if their sadness persists in the absence of other symptoms, they may well want, or feel they “should” have medications, even in the absence of a disorder. And maybe those medications help them feel better, so that the presence or absence of a verified illness doesn’t really matter. But if the medications cause adverse reactions, then psychiatry might have done a better job by that person’s sadness. Melancholia, or perhaps any designation than “depression,” with its multiple meanings, might better serve our patients and our profession. This is only one example, as the number of people who tell me they have obsessive-compulsive disorder – or more often announce, “I’m OCD!” because they are well organized in a productive way is remarkable. And while I have treated only a few people who meet the criteria for narcissistic personality disorder, from general conversation it would seem that they are at every dinner table and by every water cooler.

Does it matter? A diagnostic lexicon can be so helpful when it guides treatment, provides a heterogeneous group of patients for research studies, and allows for an understanding of the etiology, course, and prognosis of a given condition. When someone is so depressed that they can’t get out of bed, or is so disorganized that they can’t perform their job and might cause a disturbance in their workplace, it is good to instruct them to take time off work and send them back well with a doctor’s note. But this is different from the person who doesn’t want to face a difficult situation, who simply doesn’t like their job or their boss, or who wants their pet declared an emotional support animal to avoid the fee the airlines charge to bring an animal on board if one does not have a psychiatric diagnosis. Sometimes these lines are blurry – if someone does not want to do something because it makes them anxious, does it matter how deep the pit in their stomach is, or if they are having full-blown panic attacks? When do we agree that their distress is reason to allow them to avoid responsibilities without repercussions versus a violation of their obligations and an infringement on others?

Diagnoses offer solace to some patients: There is a name for their suffering, available treatment, and often others with the same condition to look to for guidance and community. For others, a psychiatric diagnosis is a source of shame, a label they see as damaging to their character and sometimes to their careers – including in medicine – where we have been particularly unsympathetic to those who announce a psychiatric history.

In some cultures, the label itself decreases someone’s attractiveness as a potential marriage partner. We would all like to see the stigma of mental illness vanish, but we have a long way to go.

Psychiatric diagnoses move over time and with our politics and culture. This is good; we don’t hold on to what we learn to be untrue. But they may well add to issues of inequity. Those who can afford to pay for expensive educational assessments can request educational accommodations, including untimed standardized tests. This advantage may not be available to those without the resources to pay for these evaluations, and one might wonder why all comers can’t take untimed tests so as not to favor the privileged. Psychiatry has long been accused of diagnosing people of color with poor prognosis illnesses and women with conditions that imply emotional weakness.

While our diagnoses have clinical utility, it is unfortunate that they have come to be about reimbursement. A diagnosis needs to be assigned for insurers to pay for care, and so we create diagnostic categories to allow for treatment. Is this reasonable? Do we need to say that someone who is suffering after the death of a loved one has a mental illness in order to allow them to seek relief from their suffering? It leads us to believe that all suffering is about pathology, that we should expect pain-free emotional lives. Perhaps we need a diagnostic category of psychic pain, not otherwise specified, to allow for treatment for those who simply ache.

Mental illness is about interventions to alleviate the suffering of those with disorders. Mental health is about interventions that may benefit everyone, whether they suffer from a mental illness or not. Sleep, nutrition, exercise, sunlight, nature, entertainment and escape, yoga, meditation, vacations in beautiful places with loving people – these are things that potentially help us all whether we do or do not have an illness. With so much confusion about what it is we do, and about who “should” get help, who can get help, who might want help, and where they should go to seek help, perhaps it would be better if our lingo were more precise.

Dr. Miller is coauthor of “Committed: The Battle Over Involuntary Psychiatric Care” (Baltimore: Johns Hopkins University Press, 2016). The has a private practice and is assistant professor of psychiatry ad behavioral sciences at Johns Hopkins University, both in Baltimore. She has no disclosures.

I am a psychiatrist, which means I am a mental health professional, which means I work with people with mental illness. Sometimes people with mental health conditions who suffer from mental illness need to take a day off work – also called a mental health day – because they are too symptomatic to work, and sometimes people who don’t have a mental illness need to take a day off work, also called a mental health day, because they are feeling stressed.

Sometimes professional athletes don’t do things they agreed to do in their contracts because they realize that doing these things is very upsetting and will be detrimental to their mental health, or maybe they have a mental illness and doing these things will worsen their mental health condition, which is, in fact, a mental illness. Other times people with mental health conditions need to have pets travel with them because this mitigates the symptoms of their mental illness or perhaps it’s just good for their mental health. And finally, some people suffer from mental illnesses, or sometimes from learning problems, which are severe enough that a person with these conditions has a disability and needs special accommodations to function optimally in educational or occupational settings, or needs public financial support because their difficulties disable them to the point that they can’t work at all.

Is your head spinning yet? The point I am trying to make is that, as a profession, we have done an abysmal job of defining what we do, who we serve, and differentiating the fact that what someone with a psychiatric disorder needs to do to function or to alleviate emotional suffering may be entirely different from the things that everyone needs to do, regardless of whether they have a psychiatric disorder, to feel their emotional best.

The National Alliance on Mental Illness tells us that one in five Americans are suffering from a mental illness, while the Epidemiologic Catchment Area Program revealed that half of people will meet criteria for a mental illness at some point in their lives. We hear about “the mentally ill” constantly in the news – often in relation to mass shooters or homelessness – yet even psychiatrists might be pressed to define who exactly the “mentally ill” are. And how many of us could not somehow, at some time, find ourselves in 1 of the 157 disorders that DSM-5 lists – down from 365 disorders in the DSM-IV-TR?

Differentiating mental health from mental illness is just the beginning of our semantic confusion. As psychiatrists we treat major depression, and yet the illness “depression,” a syndromic constellation of symptoms, includes the key symptom of sadness. People often say they are “depressed” when they mean they are sad or demoralized, and yet, if their sadness persists in the absence of other symptoms, they may well want, or feel they “should” have medications, even in the absence of a disorder. And maybe those medications help them feel better, so that the presence or absence of a verified illness doesn’t really matter. But if the medications cause adverse reactions, then psychiatry might have done a better job by that person’s sadness. Melancholia, or perhaps any designation than “depression,” with its multiple meanings, might better serve our patients and our profession. This is only one example, as the number of people who tell me they have obsessive-compulsive disorder – or more often announce, “I’m OCD!” because they are well organized in a productive way is remarkable. And while I have treated only a few people who meet the criteria for narcissistic personality disorder, from general conversation it would seem that they are at every dinner table and by every water cooler.

Does it matter? A diagnostic lexicon can be so helpful when it guides treatment, provides a heterogeneous group of patients for research studies, and allows for an understanding of the etiology, course, and prognosis of a given condition. When someone is so depressed that they can’t get out of bed, or is so disorganized that they can’t perform their job and might cause a disturbance in their workplace, it is good to instruct them to take time off work and send them back well with a doctor’s note. But this is different from the person who doesn’t want to face a difficult situation, who simply doesn’t like their job or their boss, or who wants their pet declared an emotional support animal to avoid the fee the airlines charge to bring an animal on board if one does not have a psychiatric diagnosis. Sometimes these lines are blurry – if someone does not want to do something because it makes them anxious, does it matter how deep the pit in their stomach is, or if they are having full-blown panic attacks? When do we agree that their distress is reason to allow them to avoid responsibilities without repercussions versus a violation of their obligations and an infringement on others?

Diagnoses offer solace to some patients: There is a name for their suffering, available treatment, and often others with the same condition to look to for guidance and community. For others, a psychiatric diagnosis is a source of shame, a label they see as damaging to their character and sometimes to their careers – including in medicine – where we have been particularly unsympathetic to those who announce a psychiatric history.

In some cultures, the label itself decreases someone’s attractiveness as a potential marriage partner. We would all like to see the stigma of mental illness vanish, but we have a long way to go.

Psychiatric diagnoses move over time and with our politics and culture. This is good; we don’t hold on to what we learn to be untrue. But they may well add to issues of inequity. Those who can afford to pay for expensive educational assessments can request educational accommodations, including untimed standardized tests. This advantage may not be available to those without the resources to pay for these evaluations, and one might wonder why all comers can’t take untimed tests so as not to favor the privileged. Psychiatry has long been accused of diagnosing people of color with poor prognosis illnesses and women with conditions that imply emotional weakness.

While our diagnoses have clinical utility, it is unfortunate that they have come to be about reimbursement. A diagnosis needs to be assigned for insurers to pay for care, and so we create diagnostic categories to allow for treatment. Is this reasonable? Do we need to say that someone who is suffering after the death of a loved one has a mental illness in order to allow them to seek relief from their suffering? It leads us to believe that all suffering is about pathology, that we should expect pain-free emotional lives. Perhaps we need a diagnostic category of psychic pain, not otherwise specified, to allow for treatment for those who simply ache.

Mental illness is about interventions to alleviate the suffering of those with disorders. Mental health is about interventions that may benefit everyone, whether they suffer from a mental illness or not. Sleep, nutrition, exercise, sunlight, nature, entertainment and escape, yoga, meditation, vacations in beautiful places with loving people – these are things that potentially help us all whether we do or do not have an illness. With so much confusion about what it is we do, and about who “should” get help, who can get help, who might want help, and where they should go to seek help, perhaps it would be better if our lingo were more precise.

Dr. Miller is coauthor of “Committed: The Battle Over Involuntary Psychiatric Care” (Baltimore: Johns Hopkins University Press, 2016). The has a private practice and is assistant professor of psychiatry ad behavioral sciences at Johns Hopkins University, both in Baltimore. She has no disclosures.

A small, open-label, randomized trial of patients with chronic pain from hip and knee osteoarthritis in the Netherlands shows that adding duloxetine to usual care doesn’t significantly improve clinical outcomes.

The results, published on Jan. 6 in Arthritis & Rheumatology, also showed duloxetine did not affect outcomes for a subgroup of patients who had symptoms of centrally sensitized pain, according to Jacoline J. van den Driest, MD, of the department of general practice at Erasmus University Medical Center, Rotterdam, the Netherlands, and colleagues.

The researchers acknowledged their findings contrast with other studies that showed a “small to moderate effect of duloxetine” for patients with chronic pain from hip and knee OA. There was also a higher rate of discontinuation of duloxetine around 3 months in the current trial, compared with previous studies, the authors said, which they attributed to the fact that clinicians were asked to discontinue treatment at 3 months if patients saw no effect or increased side effects.

“This difference in outcome can be due to the fact that we studied the effectiveness of duloxetine in primary care, while the other studies examined the efficacy in placebo-controlled trials in secondary care,” the researchers wrote. Patients in the current trial were also older, had more comorbidities, and had been living with OA symptoms “for a longer time” than patients in other trials, they explained.

“It is known that, in these more ‘real-life’ primary care populations and in effectiveness studies, smaller effects are found than in highly controlled efficacy trials,” they noted.

Dr. van den Driest and colleagues evaluated 132 patients with hip or knee OA between January 2016 and February 2019 who were cluster randomized at 66 general practitioner practice sites to receive duloxetine (30 mg/day in the first week, 60 mg/day in the second week and beyond) in addition to usual care that consisted of analgesics, physiotherapy, patient education, diet, and lifestyle advice. Patients were included in the study if they were at least 18 years old, met the American College of Rheumatology criteria for hip or knee OA, and experienced chronic pain for “most days” over 3 months that was not improved through use of NSAIDs or acetaminophen or were unable to use NSAIDs because of contraindications or adverse effects. They were excluded if taking duloxetine was contraindicated for them, if they were taking an antidepressant or neuropathic pain medication, and if they had rheumatoid arthritis or were scheduled for total hip or total knee replacement.

The researchers assessed patients’ Western Ontario McMaster Universities (WOMAC) Osteoarthritis Index pain scores at 3 months, compared with baseline, as a primary outcome, with secondary outcomes of WOMAC pain and function at 1 year, and cost-effectiveness as measured by the EQ-5D-5L. A modified painDETECT questionnaire was also used at baseline to identify a subset of patients with presence of centralized pain, which was defined as a score >12.

At 12 months, 80.3% of patients in both groups completed follow-up. Patient characteristics differed in duloxetine and usual-care groups, with the duloxetine group being younger (63.2 years vs. 65.4 years) and having fewer women (59.1% vs. 75.8%). The duloxetine group also had a lower percentage of patients with knee OA (77.3% vs. 86.4%) and a lower percentage of patients with two or more comorbidities (15.2% vs. 33.2%).

Duloxetine led to a nonsignificant improvement in WOMAC-measured pain at 3 months, compared with usual care (adjusted difference, –0.58; 95% confidence interval, –1.80 to 0.63), and at 12 months (adjusted difference, –0.26; 95% CI, –1.86 to 1.34). Among a subgroup of patients with central sensitization symptoms, there was a nonsignificant improvement in WOMAC-measured pain at 3 months (adjusted difference, –0.32; 95% CI, –2.32 to 1.67) and 12 months (adjusted difference, 1.02; 95% CI, –1.22 to 3.27).

Duloxetine also did not significantly improve WOMAC-measured function at 3 months (adjusted difference, –2.10; 95% CI, –6.39 to 2.20) or 12 months (adjusted difference, –1.79; 95% CI, –7.22 to 3.64).

For other secondary outcomes of quality of life, patient satisfaction, and Outcome Measures in Rheumatology (OMERACT)-Osteoarthritis Research Society International (OARSI) responder criteria, Dr. van den Driest and colleagues noted that “none of the differences between the two groups were clinically relevant or statistically significant.”

Some patients may likely still benefit from duloxetine
Commenting on the results, Joshua F. Baker, MD, MSCE, associate professor of rheumatology and epidemiology at the University of Pennsylvania and Philadelphia VA Medical Center, said the study by van den Driest and colleagues is pragmatic and demonstrates the “ ‘real-world’ benefits of trying duloxetine” – one of the study’s strengths.

“As we would probably expect, the benefits are small, and somewhat smaller in this setting than what was observed in more standard clinical trials evaluating this question,” he said, noting that the study is limited by a small sample size and loss to follow-up, as well as its open-label design and the fact that most patients stopped treatment during follow-up.

Dr. Baker also explained that while patients on average did not have a meaningful effect after taking duloxetine, “that doesn’t mean that the therapy didn’t have a meaningful effect for some people.” 

“In fact, though most people didn’t receive a meaningful benefit in this study, some did,” he said. “[A]ccording to these data, treating 8 people would be expected to result in 1 person achieving an [OMERACT-OARSI] response. That’s pretty good for a disease with few things that work.”

Future study of duloxetine should focus on who is most likely to benefit from treatment “since while most probably don’t benefit a lot, some probably do,” he said.

Dr. Baker also called attention to the questions surrounding use of antidepressants. “Use of antidepressants has been questioned by some, since the average clinical benefit is low, even for conditions like depression,” he explained. “However, some would argue that even small benefits may be important since there are few things that do work very well, and because a multimodal approach that provides multiple small benefits to patients can add up to a meaningful benefit.”

This study was funded by The Netherlands Organization for Health Research and Development. One author reported receiving grants from The Netherlands Organization for Health Research and Development, the European Union, FOREUM, and the Dutch Arthritis Association, as well as personal fees from OARSI and Pfizer. The other authors reported no relevant financial disclosures.

* This story was updated 1/6/22.

A small, open-label, randomized trial of patients with chronic pain from hip and knee osteoarthritis in the Netherlands shows that adding duloxetine to usual care doesn’t significantly improve clinical outcomes.

The results, published on Jan. 6 in Arthritis & Rheumatology, also showed duloxetine did not affect outcomes for a subgroup of patients who had symptoms of centrally sensitized pain, according to Jacoline J. van den Driest, MD, of the department of general practice at Erasmus University Medical Center, Rotterdam, the Netherlands, and colleagues.

The researchers acknowledged their findings contrast with other studies that showed a “small to moderate effect of duloxetine” for patients with chronic pain from hip and knee OA. There was also a higher rate of discontinuation of duloxetine around 3 months in the current trial, compared with previous studies, the authors said, which they attributed to the fact that clinicians were asked to discontinue treatment at 3 months if patients saw no effect or increased side effects.

“This difference in outcome can be due to the fact that we studied the effectiveness of duloxetine in primary care, while the other studies examined the efficacy in placebo-controlled trials in secondary care,” the researchers wrote. Patients in the current trial were also older, had more comorbidities, and had been living with OA symptoms “for a longer time” than patients in other trials, they explained.

“It is known that, in these more ‘real-life’ primary care populations and in effectiveness studies, smaller effects are found than in highly controlled efficacy trials,” they noted.

Dr. van den Driest and colleagues evaluated 132 patients with hip or knee OA between January 2016 and February 2019 who were cluster randomized at 66 general practitioner practice sites to receive duloxetine (30 mg/day in the first week, 60 mg/day in the second week and beyond) in addition to usual care that consisted of analgesics, physiotherapy, patient education, diet, and lifestyle advice. Patients were included in the study if they were at least 18 years old, met the American College of Rheumatology criteria for hip or knee OA, and experienced chronic pain for “most days” over 3 months that was not improved through use of NSAIDs or acetaminophen or were unable to use NSAIDs because of contraindications or adverse effects. They were excluded if taking duloxetine was contraindicated for them, if they were taking an antidepressant or neuropathic pain medication, and if they had rheumatoid arthritis or were scheduled for total hip or total knee replacement.

The researchers assessed patients’ Western Ontario McMaster Universities (WOMAC) Osteoarthritis Index pain scores at 3 months, compared with baseline, as a primary outcome, with secondary outcomes of WOMAC pain and function at 1 year, and cost-effectiveness as measured by the EQ-5D-5L. A modified painDETECT questionnaire was also used at baseline to identify a subset of patients with presence of centralized pain, which was defined as a score >12.

At 12 months, 80.3% of patients in both groups completed follow-up. Patient characteristics differed in duloxetine and usual-care groups, with the duloxetine group being younger (63.2 years vs. 65.4 years) and having fewer women (59.1% vs. 75.8%). The duloxetine group also had a lower percentage of patients with knee OA (77.3% vs. 86.4%) and a lower percentage of patients with two or more comorbidities (15.2% vs. 33.2%).

Duloxetine led to a nonsignificant improvement in WOMAC-measured pain at 3 months, compared with usual care (adjusted difference, –0.58; 95% confidence interval, –1.80 to 0.63), and at 12 months (adjusted difference, –0.26; 95% CI, –1.86 to 1.34). Among a subgroup of patients with central sensitization symptoms, there was a nonsignificant improvement in WOMAC-measured pain at 3 months (adjusted difference, –0.32; 95% CI, –2.32 to 1.67) and 12 months (adjusted difference, 1.02; 95% CI, –1.22 to 3.27).

Duloxetine also did not significantly improve WOMAC-measured function at 3 months (adjusted difference, –2.10; 95% CI, –6.39 to 2.20) or 12 months (adjusted difference, –1.79; 95% CI, –7.22 to 3.64).

For other secondary outcomes of quality of life, patient satisfaction, and Outcome Measures in Rheumatology (OMERACT)-Osteoarthritis Research Society International (OARSI) responder criteria, Dr. van den Driest and colleagues noted that “none of the differences between the two groups were clinically relevant or statistically significant.”

Some patients may likely still benefit from duloxetine
Commenting on the results, Joshua F. Baker, MD, MSCE, associate professor of rheumatology and epidemiology at the University of Pennsylvania and Philadelphia VA Medical Center, said the study by van den Driest and colleagues is pragmatic and demonstrates the “ ‘real-world’ benefits of trying duloxetine” – one of the study’s strengths.

“As we would probably expect, the benefits are small, and somewhat smaller in this setting than what was observed in more standard clinical trials evaluating this question,” he said, noting that the study is limited by a small sample size and loss to follow-up, as well as its open-label design and the fact that most patients stopped treatment during follow-up.

Dr. Baker also explained that while patients on average did not have a meaningful effect after taking duloxetine, “that doesn’t mean that the therapy didn’t have a meaningful effect for some people.” 

“In fact, though most people didn’t receive a meaningful benefit in this study, some did,” he said. “[A]ccording to these data, treating 8 people would be expected to result in 1 person achieving an [OMERACT-OARSI] response. That’s pretty good for a disease with few things that work.”

Future study of duloxetine should focus on who is most likely to benefit from treatment “since while most probably don’t benefit a lot, some probably do,” he said.

Dr. Baker also called attention to the questions surrounding use of antidepressants. “Use of antidepressants has been questioned by some, since the average clinical benefit is low, even for conditions like depression,” he explained. “However, some would argue that even small benefits may be important since there are few things that do work very well, and because a multimodal approach that provides multiple small benefits to patients can add up to a meaningful benefit.”

This study was funded by The Netherlands Organization for Health Research and Development. One author reported receiving grants from The Netherlands Organization for Health Research and Development, the European Union, FOREUM, and the Dutch Arthritis Association, as well as personal fees from OARSI and Pfizer. The other authors reported no relevant financial disclosures.

* This story was updated 1/6/22.

A small, open-label, randomized trial of patients with chronic pain from hip and knee osteoarthritis in the Netherlands shows that adding duloxetine to usual care doesn’t significantly improve clinical outcomes.

The results, published on Jan. 6 in Arthritis & Rheumatology, also showed duloxetine did not affect outcomes for a subgroup of patients who had symptoms of centrally sensitized pain, according to Jacoline J. van den Driest, MD, of the department of general practice at Erasmus University Medical Center, Rotterdam, the Netherlands, and colleagues.

The researchers acknowledged their findings contrast with other studies that showed a “small to moderate effect of duloxetine” for patients with chronic pain from hip and knee OA. There was also a higher rate of discontinuation of duloxetine around 3 months in the current trial, compared with previous studies, the authors said, which they attributed to the fact that clinicians were asked to discontinue treatment at 3 months if patients saw no effect or increased side effects.

“This difference in outcome can be due to the fact that we studied the effectiveness of duloxetine in primary care, while the other studies examined the efficacy in placebo-controlled trials in secondary care,” the researchers wrote. Patients in the current trial were also older, had more comorbidities, and had been living with OA symptoms “for a longer time” than patients in other trials, they explained.

“It is known that, in these more ‘real-life’ primary care populations and in effectiveness studies, smaller effects are found than in highly controlled efficacy trials,” they noted.

Dr. van den Driest and colleagues evaluated 132 patients with hip or knee OA between January 2016 and February 2019 who were cluster randomized at 66 general practitioner practice sites to receive duloxetine (30 mg/day in the first week, 60 mg/day in the second week and beyond) in addition to usual care that consisted of analgesics, physiotherapy, patient education, diet, and lifestyle advice. Patients were included in the study if they were at least 18 years old, met the American College of Rheumatology criteria for hip or knee OA, and experienced chronic pain for “most days” over 3 months that was not improved through use of NSAIDs or acetaminophen or were unable to use NSAIDs because of contraindications or adverse effects. They were excluded if taking duloxetine was contraindicated for them, if they were taking an antidepressant or neuropathic pain medication, and if they had rheumatoid arthritis or were scheduled for total hip or total knee replacement.

The researchers assessed patients’ Western Ontario McMaster Universities (WOMAC) Osteoarthritis Index pain scores at 3 months, compared with baseline, as a primary outcome, with secondary outcomes of WOMAC pain and function at 1 year, and cost-effectiveness as measured by the EQ-5D-5L. A modified painDETECT questionnaire was also used at baseline to identify a subset of patients with presence of centralized pain, which was defined as a score >12.

At 12 months, 80.3% of patients in both groups completed follow-up. Patient characteristics differed in duloxetine and usual-care groups, with the duloxetine group being younger (63.2 years vs. 65.4 years) and having fewer women (59.1% vs. 75.8%). The duloxetine group also had a lower percentage of patients with knee OA (77.3% vs. 86.4%) and a lower percentage of patients with two or more comorbidities (15.2% vs. 33.2%).

Duloxetine led to a nonsignificant improvement in WOMAC-measured pain at 3 months, compared with usual care (adjusted difference, –0.58; 95% confidence interval, –1.80 to 0.63), and at 12 months (adjusted difference, –0.26; 95% CI, –1.86 to 1.34). Among a subgroup of patients with central sensitization symptoms, there was a nonsignificant improvement in WOMAC-measured pain at 3 months (adjusted difference, –0.32; 95% CI, –2.32 to 1.67) and 12 months (adjusted difference, 1.02; 95% CI, –1.22 to 3.27).

Duloxetine also did not significantly improve WOMAC-measured function at 3 months (adjusted difference, –2.10; 95% CI, –6.39 to 2.20) or 12 months (adjusted difference, –1.79; 95% CI, –7.22 to 3.64).

For other secondary outcomes of quality of life, patient satisfaction, and Outcome Measures in Rheumatology (OMERACT)-Osteoarthritis Research Society International (OARSI) responder criteria, Dr. van den Driest and colleagues noted that “none of the differences between the two groups were clinically relevant or statistically significant.”

Some patients may likely still benefit from duloxetine
Commenting on the results, Joshua F. Baker, MD, MSCE, associate professor of rheumatology and epidemiology at the University of Pennsylvania and Philadelphia VA Medical Center, said the study by van den Driest and colleagues is pragmatic and demonstrates the “ ‘real-world’ benefits of trying duloxetine” – one of the study’s strengths.

“As we would probably expect, the benefits are small, and somewhat smaller in this setting than what was observed in more standard clinical trials evaluating this question,” he said, noting that the study is limited by a small sample size and loss to follow-up, as well as its open-label design and the fact that most patients stopped treatment during follow-up.

Dr. Baker also explained that while patients on average did not have a meaningful effect after taking duloxetine, “that doesn’t mean that the therapy didn’t have a meaningful effect for some people.” 

“In fact, though most people didn’t receive a meaningful benefit in this study, some did,” he said. “[A]ccording to these data, treating 8 people would be expected to result in 1 person achieving an [OMERACT-OARSI] response. That’s pretty good for a disease with few things that work.”

Future study of duloxetine should focus on who is most likely to benefit from treatment “since while most probably don’t benefit a lot, some probably do,” he said.

Dr. Baker also called attention to the questions surrounding use of antidepressants. “Use of antidepressants has been questioned by some, since the average clinical benefit is low, even for conditions like depression,” he explained. “However, some would argue that even small benefits may be important since there are few things that do work very well, and because a multimodal approach that provides multiple small benefits to patients can add up to a meaningful benefit.”

This study was funded by The Netherlands Organization for Health Research and Development. One author reported receiving grants from The Netherlands Organization for Health Research and Development, the European Union, FOREUM, and the Dutch Arthritis Association, as well as personal fees from OARSI and Pfizer. The other authors reported no relevant financial disclosures.

* This story was updated 1/6/22.

Jennifer Brown, MD, PhD, from the Dana-Farber Cancer Institute, highlights findings from chronic lymphocytic leukemia (CLL) studies presented at the 2021 American Society of Hematology (ASH) Annual Meeting.  

Dr Brown begins with several studies in the front-line setting. The CLL13 trial compared three venetoclax CD20 antibody regimens in young, fit patients. Most notably, obinutuzumab plus venetoclax demonstrated superiority over chemoimmunotherapy. 

Next, Dr Brown shares results from the FLAIR trial, in which oral ibrutinib plus intravenous rituximab showed superior progression-free survival over oral fludarabine, oral cyclophosphamide, and intravenous rituximab (FCR). 

She also discusses long-term results from a study of ibrutinib plus FCR in younger patients. The rate of undetectable minimal residual disease was sustained and the rate of complete remission increased compared with the initial analysis. 

Dr Brown also reports that in the SEQUOIA trial, zanubrutinib demonstrated superiority in progression-free survival, even in high-risk subgroups. 

In the relapsed/refractory setting, Dr Brown looks at the BRUIN study, in which pirtobrutinib demonstrated promising efficacy in patients who were previously treated with Bruton tyrosine kinase (BTK) inhibitors, as well as promising early data on the novel covalent inhibitor MK-1026.  

Dr Brown concludes with a review of two studies of humoral and T-cell responses to COVID-19 vaccines in patients with CLL, which both underscored the importance of vaccinations, boosters, and follow-up doses in this group. 

--

Jennifer Brown, MD, PhD, Worthington and Margaret Collette Professor of Medicine, Harvard Medical School; Institute Physician, Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham & Women's Hospital, Boston, Massachusetts  

Jennifer Brown, MD, PhD, has disclosed the following relevant financial relationships:  

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: AbbVie; Acerta/AstraZeneca; BeiGene; Catapult; Genentech/Roche; Hutchmed; Janssen; MEI Pharma 

Received research grant from: Gilead; Loxo/Lilly; TG Therapeutics; Verastem/SecuraBio 

Jennifer Brown, MD, PhD, from the Dana-Farber Cancer Institute, highlights findings from chronic lymphocytic leukemia (CLL) studies presented at the 2021 American Society of Hematology (ASH) Annual Meeting.  

Dr Brown begins with several studies in the front-line setting. The CLL13 trial compared three venetoclax CD20 antibody regimens in young, fit patients. Most notably, obinutuzumab plus venetoclax demonstrated superiority over chemoimmunotherapy. 

Next, Dr Brown shares results from the FLAIR trial, in which oral ibrutinib plus intravenous rituximab showed superior progression-free survival over oral fludarabine, oral cyclophosphamide, and intravenous rituximab (FCR). 

She also discusses long-term results from a study of ibrutinib plus FCR in younger patients. The rate of undetectable minimal residual disease was sustained and the rate of complete remission increased compared with the initial analysis. 

Dr Brown also reports that in the SEQUOIA trial, zanubrutinib demonstrated superiority in progression-free survival, even in high-risk subgroups. 

In the relapsed/refractory setting, Dr Brown looks at the BRUIN study, in which pirtobrutinib demonstrated promising efficacy in patients who were previously treated with Bruton tyrosine kinase (BTK) inhibitors, as well as promising early data on the novel covalent inhibitor MK-1026.  

Dr Brown concludes with a review of two studies of humoral and T-cell responses to COVID-19 vaccines in patients with CLL, which both underscored the importance of vaccinations, boosters, and follow-up doses in this group. 

--

Jennifer Brown, MD, PhD, Worthington and Margaret Collette Professor of Medicine, Harvard Medical School; Institute Physician, Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham & Women's Hospital, Boston, Massachusetts  

Jennifer Brown, MD, PhD, has disclosed the following relevant financial relationships:  

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: AbbVie; Acerta/AstraZeneca; BeiGene; Catapult; Genentech/Roche; Hutchmed; Janssen; MEI Pharma 

Received research grant from: Gilead; Loxo/Lilly; TG Therapeutics; Verastem/SecuraBio 

Jennifer Brown, MD, PhD, from the Dana-Farber Cancer Institute, highlights findings from chronic lymphocytic leukemia (CLL) studies presented at the 2021 American Society of Hematology (ASH) Annual Meeting.  

Dr Brown begins with several studies in the front-line setting. The CLL13 trial compared three venetoclax CD20 antibody regimens in young, fit patients. Most notably, obinutuzumab plus venetoclax demonstrated superiority over chemoimmunotherapy. 

Next, Dr Brown shares results from the FLAIR trial, in which oral ibrutinib plus intravenous rituximab showed superior progression-free survival over oral fludarabine, oral cyclophosphamide, and intravenous rituximab (FCR). 

She also discusses long-term results from a study of ibrutinib plus FCR in younger patients. The rate of undetectable minimal residual disease was sustained and the rate of complete remission increased compared with the initial analysis. 

Dr Brown also reports that in the SEQUOIA trial, zanubrutinib demonstrated superiority in progression-free survival, even in high-risk subgroups. 

In the relapsed/refractory setting, Dr Brown looks at the BRUIN study, in which pirtobrutinib demonstrated promising efficacy in patients who were previously treated with Bruton tyrosine kinase (BTK) inhibitors, as well as promising early data on the novel covalent inhibitor MK-1026.  

Dr Brown concludes with a review of two studies of humoral and T-cell responses to COVID-19 vaccines in patients with CLL, which both underscored the importance of vaccinations, boosters, and follow-up doses in this group. 

--

Jennifer Brown, MD, PhD, Worthington and Margaret Collette Professor of Medicine, Harvard Medical School; Institute Physician, Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham & Women's Hospital, Boston, Massachusetts  

Jennifer Brown, MD, PhD, has disclosed the following relevant financial relationships:  

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: AbbVie; Acerta/AstraZeneca; BeiGene; Catapult; Genentech/Roche; Hutchmed; Janssen; MEI Pharma 

Received research grant from: Gilead; Loxo/Lilly; TG Therapeutics; Verastem/SecuraBio 

Brad Kahl, MD, shares results from non-Hodgkin lymphoma clinical trials that were presented at the 2021 American Society of Hematology (ASH) Annual Meeting. 

Dr Kahl looks first at a frontline study examining a new combination therapy. The POLARIX study compared polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) with standard of care in patients with untreated diffuse large B-cell lymphoma (DLBCL). Pola-R-CHP demonstrated significant improvement in progression-free survival. 

In relapsed/refractory non-Hodgkin lymphoma, Dr Kahl highlights several studies in chimeric antigen receptor (CAR) T-cell therapy. He starts with a primary analysis of the ZUMA-7 trial, in which axicabtagene ciloleucel (axi-cel) demonstrated improved survival compared with standard of care in patients with relapsed/refractory DLBCL. 

Next, he reports on the TRANSFORM study, which compared lisocabtagene maraleucel (liso-cel) with standard of care in the second-line setting for patients with high-risk relapsed/refractory DLBCL. Liso-cel demonstrated favorable outcomes, with improved event-free survival and no new safety concerns. 

The third CAR T-cell study he discusses is an updated analysis from ZUMA-5 that shows longer-term data for axi-cel in patients with relapsed/refractory follicular lymphoma or marginal zone lymphoma. Consistent with the primary analysis, this study demonstrated positive survival and safety outcomes in both groups. 

Finally, Dr Kahl examines a phase 1/2 study of mosunetuzumab monotherapy for patients with relapsed/refractory follicular lymphoma who have received at least two lines of therapy. The study demonstrated improved response rates and favorable safety results.

--

Brad Kahl, MD, Professor of Medicine, Department of Medical Oncology; Director, Lymphoma Program, Washington University School of Medicine, St. Louis, Missouri 
 

Brad Kahl, MD, has disclosed the following relevant financial relationships:  

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: AbbVie; ADC Therapeutics; AstraZeneca; BeiGene; Celgene: Epizyme; Genentech; Pharmacyclics; Roche; TG Therapeutics 

Received income in an amount equal to or greater than $250 from: Genentech; AbbVie; Janssen 

Brad Kahl, MD, shares results from non-Hodgkin lymphoma clinical trials that were presented at the 2021 American Society of Hematology (ASH) Annual Meeting. 

Dr Kahl looks first at a frontline study examining a new combination therapy. The POLARIX study compared polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) with standard of care in patients with untreated diffuse large B-cell lymphoma (DLBCL). Pola-R-CHP demonstrated significant improvement in progression-free survival. 

In relapsed/refractory non-Hodgkin lymphoma, Dr Kahl highlights several studies in chimeric antigen receptor (CAR) T-cell therapy. He starts with a primary analysis of the ZUMA-7 trial, in which axicabtagene ciloleucel (axi-cel) demonstrated improved survival compared with standard of care in patients with relapsed/refractory DLBCL. 

Next, he reports on the TRANSFORM study, which compared lisocabtagene maraleucel (liso-cel) with standard of care in the second-line setting for patients with high-risk relapsed/refractory DLBCL. Liso-cel demonstrated favorable outcomes, with improved event-free survival and no new safety concerns. 

The third CAR T-cell study he discusses is an updated analysis from ZUMA-5 that shows longer-term data for axi-cel in patients with relapsed/refractory follicular lymphoma or marginal zone lymphoma. Consistent with the primary analysis, this study demonstrated positive survival and safety outcomes in both groups. 

Finally, Dr Kahl examines a phase 1/2 study of mosunetuzumab monotherapy for patients with relapsed/refractory follicular lymphoma who have received at least two lines of therapy. The study demonstrated improved response rates and favorable safety results.

--

Brad Kahl, MD, Professor of Medicine, Department of Medical Oncology; Director, Lymphoma Program, Washington University School of Medicine, St. Louis, Missouri 
 

Brad Kahl, MD, has disclosed the following relevant financial relationships:  

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: AbbVie; ADC Therapeutics; AstraZeneca; BeiGene; Celgene: Epizyme; Genentech; Pharmacyclics; Roche; TG Therapeutics 

Received income in an amount equal to or greater than $250 from: Genentech; AbbVie; Janssen 

Brad Kahl, MD, shares results from non-Hodgkin lymphoma clinical trials that were presented at the 2021 American Society of Hematology (ASH) Annual Meeting. 

Dr Kahl looks first at a frontline study examining a new combination therapy. The POLARIX study compared polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) with standard of care in patients with untreated diffuse large B-cell lymphoma (DLBCL). Pola-R-CHP demonstrated significant improvement in progression-free survival. 

In relapsed/refractory non-Hodgkin lymphoma, Dr Kahl highlights several studies in chimeric antigen receptor (CAR) T-cell therapy. He starts with a primary analysis of the ZUMA-7 trial, in which axicabtagene ciloleucel (axi-cel) demonstrated improved survival compared with standard of care in patients with relapsed/refractory DLBCL. 

Next, he reports on the TRANSFORM study, which compared lisocabtagene maraleucel (liso-cel) with standard of care in the second-line setting for patients with high-risk relapsed/refractory DLBCL. Liso-cel demonstrated favorable outcomes, with improved event-free survival and no new safety concerns. 

The third CAR T-cell study he discusses is an updated analysis from ZUMA-5 that shows longer-term data for axi-cel in patients with relapsed/refractory follicular lymphoma or marginal zone lymphoma. Consistent with the primary analysis, this study demonstrated positive survival and safety outcomes in both groups. 

Finally, Dr Kahl examines a phase 1/2 study of mosunetuzumab monotherapy for patients with relapsed/refractory follicular lymphoma who have received at least two lines of therapy. The study demonstrated improved response rates and favorable safety results.

--

Brad Kahl, MD, Professor of Medicine, Department of Medical Oncology; Director, Lymphoma Program, Washington University School of Medicine, St. Louis, Missouri 
 

Brad Kahl, MD, has disclosed the following relevant financial relationships:  

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: AbbVie; ADC Therapeutics; AstraZeneca; BeiGene; Celgene: Epizyme; Genentech; Pharmacyclics; Roche; TG Therapeutics 

Received income in an amount equal to or greater than $250 from: Genentech; AbbVie; Janssen 

Ian Flinn, MD, PhD, director of lymphoma research at the Sarah Cannon Cancer Institute, highlights findings in Hodgkin lymphoma presented at the 2021 meeting of the American Society of Hematology. 

The first study that Dr Flinn discusses combined pembrolizumab with AVD in patients with untreated Hodgkin lymphoma. This regimen was found to be both safe and effective, with high overall response, progression-free survival, and overall survival rates. 

Another study he examines combined pembrolizumab with ICE chemotherapy prior to autologous hematologic stem cell transplant. The primary endpoint of complete metabolic response was met and the regimen demonstrated a tolerable safety profile. 

Next, Dr Flinn looks at a study comparing seven novel and conventional salvage therapies. Most notably, brentuximab vedotin plus nivolumab demonstrated a higher complete remission rate and better post-autologous stem cell transplant progression-free survival compared with chemotherapy. 

Dr Flinn concludes with a phase 2 study that evaluated first-line nivolumab in older frail patients. The primary objective of complete metabolic response rate was not reached, with safety findings comparable to those of published data in this population. 

--

Ian W. Flinn, MD, PhD, Director, Lymphoma Research; Principal Investigator, Sarah Cannon Cancer Institute, Nashville, Tennessee 

Ian W. Flinn, MD, PhD, has disclosed the following relevant financial relationships: 

Serve(d) as a consultant: AbbVie; AstraZeneca; BeiGene; Century Therapeutics; Genentech; Gilead Sciences; Great Point Partners; Hutchison MediPharma; Iksuda Therapeutics; Janssen; Juno Therapeutics; Kite Pharma; MorphoSys; Novartis; Nurix Therapeutics; Pharmacyclics; Roche; Seattle Genetics; Takeda; TG Therapeutics; Unum Therapeutics; Verastem; Vincerx Pharma; Yingli Pharmaceuticals 

Institute received research grant from: AbbVie; Acerta Pharma; Agios; ArQule; AstraZeneca; BeiGene; Calithera Biosciences; Celgene; Constellation Pharmaceuticals; Curis; Forma Therapeutics; Forty Seven; Genentech; Gilead Sciences; IGM Biosciences; Incyte; Infinity Pharmaceuticals; Janssen; Juno Therapeutics; Karyopharm Therapeutics; Kite Pharma; Loxo; Merck; MorphoSys; Novartis; Pfizer; Pharmacyclics; Portola Pharmaceuticals; Rhizen Pharmaceuticals; Roche; Seattle Genetics; Takeda; Teva Pharmaceuticals; TG Therapeutics; Trillium Therapeutics; Triphase Research & Development; Unum Therapeutics; Verastem 

Ian Flinn, MD, PhD, director of lymphoma research at the Sarah Cannon Cancer Institute, highlights findings in Hodgkin lymphoma presented at the 2021 meeting of the American Society of Hematology. 

The first study that Dr Flinn discusses combined pembrolizumab with AVD in patients with untreated Hodgkin lymphoma. This regimen was found to be both safe and effective, with high overall response, progression-free survival, and overall survival rates. 

Another study he examines combined pembrolizumab with ICE chemotherapy prior to autologous hematologic stem cell transplant. The primary endpoint of complete metabolic response was met and the regimen demonstrated a tolerable safety profile. 

Next, Dr Flinn looks at a study comparing seven novel and conventional salvage therapies. Most notably, brentuximab vedotin plus nivolumab demonstrated a higher complete remission rate and better post-autologous stem cell transplant progression-free survival compared with chemotherapy. 

Dr Flinn concludes with a phase 2 study that evaluated first-line nivolumab in older frail patients. The primary objective of complete metabolic response rate was not reached, with safety findings comparable to those of published data in this population. 

--

Ian W. Flinn, MD, PhD, Director, Lymphoma Research; Principal Investigator, Sarah Cannon Cancer Institute, Nashville, Tennessee 

Ian W. Flinn, MD, PhD, has disclosed the following relevant financial relationships: 

Serve(d) as a consultant: AbbVie; AstraZeneca; BeiGene; Century Therapeutics; Genentech; Gilead Sciences; Great Point Partners; Hutchison MediPharma; Iksuda Therapeutics; Janssen; Juno Therapeutics; Kite Pharma; MorphoSys; Novartis; Nurix Therapeutics; Pharmacyclics; Roche; Seattle Genetics; Takeda; TG Therapeutics; Unum Therapeutics; Verastem; Vincerx Pharma; Yingli Pharmaceuticals 

Institute received research grant from: AbbVie; Acerta Pharma; Agios; ArQule; AstraZeneca; BeiGene; Calithera Biosciences; Celgene; Constellation Pharmaceuticals; Curis; Forma Therapeutics; Forty Seven; Genentech; Gilead Sciences; IGM Biosciences; Incyte; Infinity Pharmaceuticals; Janssen; Juno Therapeutics; Karyopharm Therapeutics; Kite Pharma; Loxo; Merck; MorphoSys; Novartis; Pfizer; Pharmacyclics; Portola Pharmaceuticals; Rhizen Pharmaceuticals; Roche; Seattle Genetics; Takeda; Teva Pharmaceuticals; TG Therapeutics; Trillium Therapeutics; Triphase Research & Development; Unum Therapeutics; Verastem 

Ian Flinn, MD, PhD, director of lymphoma research at the Sarah Cannon Cancer Institute, highlights findings in Hodgkin lymphoma presented at the 2021 meeting of the American Society of Hematology. 

The first study that Dr Flinn discusses combined pembrolizumab with AVD in patients with untreated Hodgkin lymphoma. This regimen was found to be both safe and effective, with high overall response, progression-free survival, and overall survival rates. 

Another study he examines combined pembrolizumab with ICE chemotherapy prior to autologous hematologic stem cell transplant. The primary endpoint of complete metabolic response was met and the regimen demonstrated a tolerable safety profile. 

Next, Dr Flinn looks at a study comparing seven novel and conventional salvage therapies. Most notably, brentuximab vedotin plus nivolumab demonstrated a higher complete remission rate and better post-autologous stem cell transplant progression-free survival compared with chemotherapy. 

Dr Flinn concludes with a phase 2 study that evaluated first-line nivolumab in older frail patients. The primary objective of complete metabolic response rate was not reached, with safety findings comparable to those of published data in this population. 

--

Ian W. Flinn, MD, PhD, Director, Lymphoma Research; Principal Investigator, Sarah Cannon Cancer Institute, Nashville, Tennessee 

Ian W. Flinn, MD, PhD, has disclosed the following relevant financial relationships: 

Serve(d) as a consultant: AbbVie; AstraZeneca; BeiGene; Century Therapeutics; Genentech; Gilead Sciences; Great Point Partners; Hutchison MediPharma; Iksuda Therapeutics; Janssen; Juno Therapeutics; Kite Pharma; MorphoSys; Novartis; Nurix Therapeutics; Pharmacyclics; Roche; Seattle Genetics; Takeda; TG Therapeutics; Unum Therapeutics; Verastem; Vincerx Pharma; Yingli Pharmaceuticals 

Institute received research grant from: AbbVie; Acerta Pharma; Agios; ArQule; AstraZeneca; BeiGene; Calithera Biosciences; Celgene; Constellation Pharmaceuticals; Curis; Forma Therapeutics; Forty Seven; Genentech; Gilead Sciences; IGM Biosciences; Incyte; Infinity Pharmaceuticals; Janssen; Juno Therapeutics; Karyopharm Therapeutics; Kite Pharma; Loxo; Merck; MorphoSys; Novartis; Pfizer; Pharmacyclics; Portola Pharmaceuticals; Rhizen Pharmaceuticals; Roche; Seattle Genetics; Takeda; Teva Pharmaceuticals; TG Therapeutics; Trillium Therapeutics; Triphase Research & Development; Unum Therapeutics; Verastem 

The recently developed ACE index – which incorporates three variables at hospital admission (C-reactive protein [CRP], albumin, and endoscopic severity) – accurately predicts steroid response at hospital admission in patients with acute severe ulcerative colitis (ASUC). This is according to study findings presented at the annual Advances in Inflammatory Bowel Diseases conference by Marta Freitas, MD, of the Senhora da Oliveira Hospital in Guimarães, Portugal.*

Although intravenous steroids represent the first-line medical therapy for patients admitted to the hospital with acute UC, one study found that approximately 30% of patients with ASUC do not respond to this treatment approach and therefore require more advanced management options.

In patients with ASUC, delays in initiating therapy may be associated with an increased risk of mortality, explained Dr. Freitas and colleagues. Given this risk, there is a need for sensitive and accurate tools that can identify patients at admission who are at high risk of steroid nonresponse and who may likewise receive benefit from surgical intervention or earlier second-line therapy.

Early prediction of response to steroids in patients with ASUC at time of admission could also be helpful for prioritizing further assessment and counseling. The ACE index was recently developed to identify these patients to help improve risk stratification and facilitate earlier treatment delivery. A combination of three parameters is found within the ACE index: albumin ≤30 g/L; CRP ≥50 mg/L; and increased endoscopic severity as defined by a Mayo endoscopic score of 3.

Dr. Freitas and researchers retrospectively evaluated the performance of the ACE index in predicting steroid response in 65 patients with ASUC (mean age, 34 years). The study included a review of admissions for the disease between 2005 and 2020. The accuracy of the ACE index score was evaluated through the area under the curve.

Approximately 78.5% of patients in the retrospective cohort study had responded to steroids. Compared with nonresponders, responders had significantly different mean CRP (108.0 ± 60.0 vs. 66.0 ± 53.2 mg/dL, respectively; P = .01), mean albumin (2.9 ± 0.66 vs. 3.4 ± 0.71 g/L; P = .02), and median endoscopic severity score (3 vs. 3; interquartile range, 1 vs. 0; P = .005) at admission. In contrast, no statistically significant difference was found between responders versus nonresponders in regard to the median UC Endoscopic Index of Severity (UCEIS) score (8 vs. 7; P = .28).

Overall, the median ACE index score was 2. Steroid nonresponders had a significantly higher ACE index score (2.5 vs. 1; P = .001). The researchers noted that the ACE index score was a significant predictor of steroid response (AUC, 0.789; P = .001). Half (50.0%) of patients with an ACE index score of 3 had no response to steroids, while 86.3% of patients who had an ACE index score lower than 3 experienced a steroid response.

In a poster presentation by Hartman Brunt, MD, of the Louisiana State University Health Sciences Center in Baton Rouge, real-world data suggest there exists several inconsistencies in the use of UC-monitoring strategies recommended by clinical practice guidelines. According to a single-center retrospective chart review of adult patients with moderate to severe UC, Dr. Brunt and colleagues found that measurement of CRP decreased over time as did measurement of fecal calprotectin.

Given the lack of standardization for IBD monitoring, Dr. Hartman and colleagues noted “there is inevitably increased variability in provider care.” Consequently, this variability and lack of guideline adherence may lead to heterogeneous effects among the IBD patient population, including those that may drive suboptimal long-term outcomes.

In addition to disease monitoring, assessment of treatment response remains highly valuable, yet no clinical guidance currently exists on the use of the ACE index score in ASUC. Further research is needed to determine the validity of the ACE Index in a larger patient population to inform future clinical practice guidelines and expert consensus statements.

Ashwin Ananthakrishnan, MBBS, a gastroenterologist from Massachusetts General Hospital in Boston, said in an email to this news organization that there is an urgent need for tools that “accurately predict treatment response in severe UC because of the higher morbidity and rate of surgery in this population.” Dr. Ananthakrishnan is a co–primary investigator of the MASCC (Multi-center Acute Severe UC Cohort Study), sponsored by Johns Hopkins University, which is investigating the ACE index and other predictors of outcomes in severe UC.

“In addition, treatment decisions need to be made fairly quickly as clinical condition may change day to day,” further emphasizing the need for these predictors, added Dr. Ananthakrishnan. “At this point, the ACE index and other prediction scores have been described from observational studies, but the key is to prospectively incorporate this into a treatment algorithm.”

Dr. Ananthakrishnan explained that patients with a high ACE index, or those with UC who satisfy the high-risk criteria of other prediction models, may benefit from early or even upfront rescue therapy rather than trying steroids for 3-5 days first. He added that “the field is not quite there, and we need more study of this” approach.

Dr. Freitas, Dr. Brunt, and Dr. Ananthakrishnan declared no relevant conflicts of interest.

This article was updated 1/11/22. 

*Correction, 1/11/22: An earlier version of this article misstated Dr. Martha Freitas' name.

The recently developed ACE index – which incorporates three variables at hospital admission (C-reactive protein [CRP], albumin, and endoscopic severity) – accurately predicts steroid response at hospital admission in patients with acute severe ulcerative colitis (ASUC). This is according to study findings presented at the annual Advances in Inflammatory Bowel Diseases conference by Marta Freitas, MD, of the Senhora da Oliveira Hospital in Guimarães, Portugal.*

Although intravenous steroids represent the first-line medical therapy for patients admitted to the hospital with acute UC, one study found that approximately 30% of patients with ASUC do not respond to this treatment approach and therefore require more advanced management options.

In patients with ASUC, delays in initiating therapy may be associated with an increased risk of mortality, explained Dr. Freitas and colleagues. Given this risk, there is a need for sensitive and accurate tools that can identify patients at admission who are at high risk of steroid nonresponse and who may likewise receive benefit from surgical intervention or earlier second-line therapy.

Early prediction of response to steroids in patients with ASUC at time of admission could also be helpful for prioritizing further assessment and counseling. The ACE index was recently developed to identify these patients to help improve risk stratification and facilitate earlier treatment delivery. A combination of three parameters is found within the ACE index: albumin ≤30 g/L; CRP ≥50 mg/L; and increased endoscopic severity as defined by a Mayo endoscopic score of 3.

Dr. Freitas and researchers retrospectively evaluated the performance of the ACE index in predicting steroid response in 65 patients with ASUC (mean age, 34 years). The study included a review of admissions for the disease between 2005 and 2020. The accuracy of the ACE index score was evaluated through the area under the curve.

Approximately 78.5% of patients in the retrospective cohort study had responded to steroids. Compared with nonresponders, responders had significantly different mean CRP (108.0 ± 60.0 vs. 66.0 ± 53.2 mg/dL, respectively; P = .01), mean albumin (2.9 ± 0.66 vs. 3.4 ± 0.71 g/L; P = .02), and median endoscopic severity score (3 vs. 3; interquartile range, 1 vs. 0; P = .005) at admission. In contrast, no statistically significant difference was found between responders versus nonresponders in regard to the median UC Endoscopic Index of Severity (UCEIS) score (8 vs. 7; P = .28).

Overall, the median ACE index score was 2. Steroid nonresponders had a significantly higher ACE index score (2.5 vs. 1; P = .001). The researchers noted that the ACE index score was a significant predictor of steroid response (AUC, 0.789; P = .001). Half (50.0%) of patients with an ACE index score of 3 had no response to steroids, while 86.3% of patients who had an ACE index score lower than 3 experienced a steroid response.

In a poster presentation by Hartman Brunt, MD, of the Louisiana State University Health Sciences Center in Baton Rouge, real-world data suggest there exists several inconsistencies in the use of UC-monitoring strategies recommended by clinical practice guidelines. According to a single-center retrospective chart review of adult patients with moderate to severe UC, Dr. Brunt and colleagues found that measurement of CRP decreased over time as did measurement of fecal calprotectin.

Given the lack of standardization for IBD monitoring, Dr. Hartman and colleagues noted “there is inevitably increased variability in provider care.” Consequently, this variability and lack of guideline adherence may lead to heterogeneous effects among the IBD patient population, including those that may drive suboptimal long-term outcomes.

In addition to disease monitoring, assessment of treatment response remains highly valuable, yet no clinical guidance currently exists on the use of the ACE index score in ASUC. Further research is needed to determine the validity of the ACE Index in a larger patient population to inform future clinical practice guidelines and expert consensus statements.

Ashwin Ananthakrishnan, MBBS, a gastroenterologist from Massachusetts General Hospital in Boston, said in an email to this news organization that there is an urgent need for tools that “accurately predict treatment response in severe UC because of the higher morbidity and rate of surgery in this population.” Dr. Ananthakrishnan is a co–primary investigator of the MASCC (Multi-center Acute Severe UC Cohort Study), sponsored by Johns Hopkins University, which is investigating the ACE index and other predictors of outcomes in severe UC.

“In addition, treatment decisions need to be made fairly quickly as clinical condition may change day to day,” further emphasizing the need for these predictors, added Dr. Ananthakrishnan. “At this point, the ACE index and other prediction scores have been described from observational studies, but the key is to prospectively incorporate this into a treatment algorithm.”

Dr. Ananthakrishnan explained that patients with a high ACE index, or those with UC who satisfy the high-risk criteria of other prediction models, may benefit from early or even upfront rescue therapy rather than trying steroids for 3-5 days first. He added that “the field is not quite there, and we need more study of this” approach.

Dr. Freitas, Dr. Brunt, and Dr. Ananthakrishnan declared no relevant conflicts of interest.

This article was updated 1/11/22. 

*Correction, 1/11/22: An earlier version of this article misstated Dr. Martha Freitas' name.

The recently developed ACE index – which incorporates three variables at hospital admission (C-reactive protein [CRP], albumin, and endoscopic severity) – accurately predicts steroid response at hospital admission in patients with acute severe ulcerative colitis (ASUC). This is according to study findings presented at the annual Advances in Inflammatory Bowel Diseases conference by Marta Freitas, MD, of the Senhora da Oliveira Hospital in Guimarães, Portugal.*

Although intravenous steroids represent the first-line medical therapy for patients admitted to the hospital with acute UC, one study found that approximately 30% of patients with ASUC do not respond to this treatment approach and therefore require more advanced management options.

In patients with ASUC, delays in initiating therapy may be associated with an increased risk of mortality, explained Dr. Freitas and colleagues. Given this risk, there is a need for sensitive and accurate tools that can identify patients at admission who are at high risk of steroid nonresponse and who may likewise receive benefit from surgical intervention or earlier second-line therapy.

Early prediction of response to steroids in patients with ASUC at time of admission could also be helpful for prioritizing further assessment and counseling. The ACE index was recently developed to identify these patients to help improve risk stratification and facilitate earlier treatment delivery. A combination of three parameters is found within the ACE index: albumin ≤30 g/L; CRP ≥50 mg/L; and increased endoscopic severity as defined by a Mayo endoscopic score of 3.

Dr. Freitas and researchers retrospectively evaluated the performance of the ACE index in predicting steroid response in 65 patients with ASUC (mean age, 34 years). The study included a review of admissions for the disease between 2005 and 2020. The accuracy of the ACE index score was evaluated through the area under the curve.

Approximately 78.5% of patients in the retrospective cohort study had responded to steroids. Compared with nonresponders, responders had significantly different mean CRP (108.0 ± 60.0 vs. 66.0 ± 53.2 mg/dL, respectively; P = .01), mean albumin (2.9 ± 0.66 vs. 3.4 ± 0.71 g/L; P = .02), and median endoscopic severity score (3 vs. 3; interquartile range, 1 vs. 0; P = .005) at admission. In contrast, no statistically significant difference was found between responders versus nonresponders in regard to the median UC Endoscopic Index of Severity (UCEIS) score (8 vs. 7; P = .28).

Overall, the median ACE index score was 2. Steroid nonresponders had a significantly higher ACE index score (2.5 vs. 1; P = .001). The researchers noted that the ACE index score was a significant predictor of steroid response (AUC, 0.789; P = .001). Half (50.0%) of patients with an ACE index score of 3 had no response to steroids, while 86.3% of patients who had an ACE index score lower than 3 experienced a steroid response.

In a poster presentation by Hartman Brunt, MD, of the Louisiana State University Health Sciences Center in Baton Rouge, real-world data suggest there exists several inconsistencies in the use of UC-monitoring strategies recommended by clinical practice guidelines. According to a single-center retrospective chart review of adult patients with moderate to severe UC, Dr. Brunt and colleagues found that measurement of CRP decreased over time as did measurement of fecal calprotectin.

Given the lack of standardization for IBD monitoring, Dr. Hartman and colleagues noted “there is inevitably increased variability in provider care.” Consequently, this variability and lack of guideline adherence may lead to heterogeneous effects among the IBD patient population, including those that may drive suboptimal long-term outcomes.

In addition to disease monitoring, assessment of treatment response remains highly valuable, yet no clinical guidance currently exists on the use of the ACE index score in ASUC. Further research is needed to determine the validity of the ACE Index in a larger patient population to inform future clinical practice guidelines and expert consensus statements.

Ashwin Ananthakrishnan, MBBS, a gastroenterologist from Massachusetts General Hospital in Boston, said in an email to this news organization that there is an urgent need for tools that “accurately predict treatment response in severe UC because of the higher morbidity and rate of surgery in this population.” Dr. Ananthakrishnan is a co–primary investigator of the MASCC (Multi-center Acute Severe UC Cohort Study), sponsored by Johns Hopkins University, which is investigating the ACE index and other predictors of outcomes in severe UC.

“In addition, treatment decisions need to be made fairly quickly as clinical condition may change day to day,” further emphasizing the need for these predictors, added Dr. Ananthakrishnan. “At this point, the ACE index and other prediction scores have been described from observational studies, but the key is to prospectively incorporate this into a treatment algorithm.”

Dr. Ananthakrishnan explained that patients with a high ACE index, or those with UC who satisfy the high-risk criteria of other prediction models, may benefit from early or even upfront rescue therapy rather than trying steroids for 3-5 days first. He added that “the field is not quite there, and we need more study of this” approach.

Dr. Freitas, Dr. Brunt, and Dr. Ananthakrishnan declared no relevant conflicts of interest.

This article was updated 1/11/22. 

*Correction, 1/11/22: An earlier version of this article misstated Dr. Martha Freitas' name.

Mutations in genes associated with cardiac and seizure disorders appear to be linked to sudden unexplained deaths in young children and may explain nearly 9% of such cases, researchers have found.

Previous studies have found de novo genetic variants – those not found in either parent but which occur for the first time in their offspring – that increase the risk of cardiac and seizure disorders, but research on sudden unexplained deaths in children (SUDC) is limited, according to Matthew Halvorsen, PhD, of the University of North Carolina at Chapel Hill, and colleagues. Most cases of SUDC occur in children aged 1-4 years, and a lack of standardized investigation systems likely leads to misclassification of these deaths, they said.

Compared with sudden infant death syndrome (SIDS), which occurs in approximately 1,400 children in the United States each year, approximately 400 children aged 1 year and older die from SUDC annually. A major obstacle to studying these cases is that so-called molecular autopsies – which incorporate genetic analysis into the postmortem examination – typically do not assess the parents’ genetic information and thus limit the ability to identify de novo mutations, they added.

In a study published in the Proceedings of the National Academy of Sciences, Dr. Halvorsen’s group obtained whole exome sequence data from 124 “trios,” meaning a dead child and two living parents. They tested for excessive de novo mutations for different genes involved in conditions that included cardiac arrhythmias and epilepsy. The average age at the time of death for the children was 34.2 months; 54% were male, and 82% were White.

Children who died of SUDC were nearly 10 times as likely to have de novo mutations in genes associated with cardiac and seizure disorders as were unrelated healthy controls (odds ratio, 9.76). Most pathogenic variants were de novo, which highlights the importance of trio studies, the researchers noted.

The researchers identified 11 variants associated with increased risk of SUDC, 7 of which were de novo. Three of the 124 cases carried mutations (two for RYR2 and 1 for TNNI3) affecting genes in the CardiacEpilepsy dataset proposed by the American College of Medical Genetics and Genomics, strengthening the connection to seizure disorders.

Another notable finding was the identification of six de novo mutations involved in altering calcium-related regulation, which suggests a cardiac susceptibility to sudden death.

The data support “novel genetic causes of pediatric sudden deaths that could be discovered with larger cohorts,” the researchers noted. Taken together, they say, the gene mutations could play a role in approximately 9% of SUDC cases.

The study findings were limited by several factors, including lack of population-based case ascertainment, exclusive focus on unexplained deaths, potentially missed mutations, and use of DNA from blood as opposed to organs, the researchers noted.

However, they concluded, “the data indicate that deleterious de novo mutations are significant genetic risk factors for childhood sudden unexplained death, and that their identification may lead to medical intervention that ultimately saves lives.”

Findings highlight impact of SUDC

“This study is important because SUDC is a much more pressing medical need than most people realize,” said Richard Tsien, PhD, of New York University Langone Medical Center, and the corresponding author of the study.

Although SUDC is less common than SIDS, SUDC has essentially no targeted research funding, Dr. Tsien said. Study coauthor Laura Gould, MA, a researcher and mother who lost a young child to SUDC, worked with Orrin Devinsky, MD, to create a registry for families with cases of SUDC. This registry was instrumental in allowing the researchers to “do the molecular detective work we need to do” to see whether a genetic basis exists for SUDC, Dr. Tsien said.

“The detective work comes up with a consistent story,” he said. “More than half of the genes that we found are involved in the normal function of the heart and brain,” performing such functions as delivering calcium ions to the inside of the heart cells and nerve cells.

The study “is the first of its kind,” given the difficulty of acquiring DNA from the child and two parents in SUDC cases, Dr. Tsien said.

Overall, approximately 10% of the cases have a compelling explanation based on the coding of DNA, Dr. Tsien said. From a clinical standpoint, that information might affect what a clinician says to a parent.

A key takeaway is that most of the genetic mutations are spontaneous and are not inherited from the parents, Dr. Tsien said. The study findings indicate that parents who suffer an SUDC loss need not be discouraged from having children, he added.

For the long term, “the more we understand about these disorders, the more information we can offer to families,” he said. Eventually, clinicians might be able to use genetics to identify signs of when SUDC might be more likely. “For example, if a child shows a very mild seizure, this would alert them that there might be potential for a more drastic outcome.”

Meanwhile, families with SUDC cases may find support and benefit in signing up for the registry and knowing that other families have been through a similar experience, Dr. Tsien said.

Genetic studies create opportunities

A significant portion of pediatric mortality remains unexplained, according to Richard D. Goldstein, MD, of Boston Children’s Hospital. One reason is the lack of a formal diagnostic code to identify these deaths.

Research to date has suggested links between SUDC and a family history of febrile seizures, as well as differences in brain structure associated with epilepsy, Dr. Goldstein said.

“An important hypothesis is that these deaths are part of a continuum that also includes stillbirths, SIDS, and sudden unexpected death in epilepsy [SUDEP],” Dr. Goldstein said. “By mandate, investigations of these deaths occur under the jurisdiction of medical examiners and coroners and have, for the most part, been insulated from developments in modern medicine like genomics and proteomics, elements of what are referred to as the molecular autopsy, and studies such as the current study bring attention to what is being missed.”

Dr. Goldstein said the new study buttresses the “conventional clinical suspicion” about the likely causes of SUDC, “but also strengthens the association between sudden unexpected death in pediatrics (SUDP) and SUDEP that we and others have been positing. I think the researchers very nicely make the point that epilepsy and cardiac arrhythmia genes are not as separated in their effects as many would believe.”

As for the clinical applicability of the findings, Dr. Goldstein said medicine needs to offer parents more: “Pediatric deaths without explanation deserve more than a forensic investigation that concerns itself mostly with whether there has been foul play,” he said. “We need to figure out how to engage families, at an incredibly vulnerable time, in helping find the cause of the child’s death and also contributing to needed research. Most of the reported variants were de novo, which means that parent participation is needed to figure out these genetic factors but also that we can offer reassurance to families that other children are not at risk.”

The study was supported by the SUDC Foundation and Finding a Cure for Epilepsy and Seizures (New York University). Dr. Tsien disclosed support from the National Institutes of Health and a grant from FACES. Dr. Goldstein reported no relevant financial relationships.

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

Mutations in genes associated with cardiac and seizure disorders appear to be linked to sudden unexplained deaths in young children and may explain nearly 9% of such cases, researchers have found.

Previous studies have found de novo genetic variants – those not found in either parent but which occur for the first time in their offspring – that increase the risk of cardiac and seizure disorders, but research on sudden unexplained deaths in children (SUDC) is limited, according to Matthew Halvorsen, PhD, of the University of North Carolina at Chapel Hill, and colleagues. Most cases of SUDC occur in children aged 1-4 years, and a lack of standardized investigation systems likely leads to misclassification of these deaths, they said.

Compared with sudden infant death syndrome (SIDS), which occurs in approximately 1,400 children in the United States each year, approximately 400 children aged 1 year and older die from SUDC annually. A major obstacle to studying these cases is that so-called molecular autopsies – which incorporate genetic analysis into the postmortem examination – typically do not assess the parents’ genetic information and thus limit the ability to identify de novo mutations, they added.

In a study published in the Proceedings of the National Academy of Sciences, Dr. Halvorsen’s group obtained whole exome sequence data from 124 “trios,” meaning a dead child and two living parents. They tested for excessive de novo mutations for different genes involved in conditions that included cardiac arrhythmias and epilepsy. The average age at the time of death for the children was 34.2 months; 54% were male, and 82% were White.

Children who died of SUDC were nearly 10 times as likely to have de novo mutations in genes associated with cardiac and seizure disorders as were unrelated healthy controls (odds ratio, 9.76). Most pathogenic variants were de novo, which highlights the importance of trio studies, the researchers noted.

The researchers identified 11 variants associated with increased risk of SUDC, 7 of which were de novo. Three of the 124 cases carried mutations (two for RYR2 and 1 for TNNI3) affecting genes in the CardiacEpilepsy dataset proposed by the American College of Medical Genetics and Genomics, strengthening the connection to seizure disorders.

Another notable finding was the identification of six de novo mutations involved in altering calcium-related regulation, which suggests a cardiac susceptibility to sudden death.

The data support “novel genetic causes of pediatric sudden deaths that could be discovered with larger cohorts,” the researchers noted. Taken together, they say, the gene mutations could play a role in approximately 9% of SUDC cases.

The study findings were limited by several factors, including lack of population-based case ascertainment, exclusive focus on unexplained deaths, potentially missed mutations, and use of DNA from blood as opposed to organs, the researchers noted.

However, they concluded, “the data indicate that deleterious de novo mutations are significant genetic risk factors for childhood sudden unexplained death, and that their identification may lead to medical intervention that ultimately saves lives.”

Findings highlight impact of SUDC

“This study is important because SUDC is a much more pressing medical need than most people realize,” said Richard Tsien, PhD, of New York University Langone Medical Center, and the corresponding author of the study.

Although SUDC is less common than SIDS, SUDC has essentially no targeted research funding, Dr. Tsien said. Study coauthor Laura Gould, MA, a researcher and mother who lost a young child to SUDC, worked with Orrin Devinsky, MD, to create a registry for families with cases of SUDC. This registry was instrumental in allowing the researchers to “do the molecular detective work we need to do” to see whether a genetic basis exists for SUDC, Dr. Tsien said.

“The detective work comes up with a consistent story,” he said. “More than half of the genes that we found are involved in the normal function of the heart and brain,” performing such functions as delivering calcium ions to the inside of the heart cells and nerve cells.

The study “is the first of its kind,” given the difficulty of acquiring DNA from the child and two parents in SUDC cases, Dr. Tsien said.

Overall, approximately 10% of the cases have a compelling explanation based on the coding of DNA, Dr. Tsien said. From a clinical standpoint, that information might affect what a clinician says to a parent.

A key takeaway is that most of the genetic mutations are spontaneous and are not inherited from the parents, Dr. Tsien said. The study findings indicate that parents who suffer an SUDC loss need not be discouraged from having children, he added.

For the long term, “the more we understand about these disorders, the more information we can offer to families,” he said. Eventually, clinicians might be able to use genetics to identify signs of when SUDC might be more likely. “For example, if a child shows a very mild seizure, this would alert them that there might be potential for a more drastic outcome.”

Meanwhile, families with SUDC cases may find support and benefit in signing up for the registry and knowing that other families have been through a similar experience, Dr. Tsien said.

Genetic studies create opportunities

A significant portion of pediatric mortality remains unexplained, according to Richard D. Goldstein, MD, of Boston Children’s Hospital. One reason is the lack of a formal diagnostic code to identify these deaths.

Research to date has suggested links between SUDC and a family history of febrile seizures, as well as differences in brain structure associated with epilepsy, Dr. Goldstein said.

“An important hypothesis is that these deaths are part of a continuum that also includes stillbirths, SIDS, and sudden unexpected death in epilepsy [SUDEP],” Dr. Goldstein said. “By mandate, investigations of these deaths occur under the jurisdiction of medical examiners and coroners and have, for the most part, been insulated from developments in modern medicine like genomics and proteomics, elements of what are referred to as the molecular autopsy, and studies such as the current study bring attention to what is being missed.”

Dr. Goldstein said the new study buttresses the “conventional clinical suspicion” about the likely causes of SUDC, “but also strengthens the association between sudden unexpected death in pediatrics (SUDP) and SUDEP that we and others have been positing. I think the researchers very nicely make the point that epilepsy and cardiac arrhythmia genes are not as separated in their effects as many would believe.”

As for the clinical applicability of the findings, Dr. Goldstein said medicine needs to offer parents more: “Pediatric deaths without explanation deserve more than a forensic investigation that concerns itself mostly with whether there has been foul play,” he said. “We need to figure out how to engage families, at an incredibly vulnerable time, in helping find the cause of the child’s death and also contributing to needed research. Most of the reported variants were de novo, which means that parent participation is needed to figure out these genetic factors but also that we can offer reassurance to families that other children are not at risk.”

The study was supported by the SUDC Foundation and Finding a Cure for Epilepsy and Seizures (New York University). Dr. Tsien disclosed support from the National Institutes of Health and a grant from FACES. Dr. Goldstein reported no relevant financial relationships.

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

Mutations in genes associated with cardiac and seizure disorders appear to be linked to sudden unexplained deaths in young children and may explain nearly 9% of such cases, researchers have found.

Previous studies have found de novo genetic variants – those not found in either parent but which occur for the first time in their offspring – that increase the risk of cardiac and seizure disorders, but research on sudden unexplained deaths in children (SUDC) is limited, according to Matthew Halvorsen, PhD, of the University of North Carolina at Chapel Hill, and colleagues. Most cases of SUDC occur in children aged 1-4 years, and a lack of standardized investigation systems likely leads to misclassification of these deaths, they said.

Compared with sudden infant death syndrome (SIDS), which occurs in approximately 1,400 children in the United States each year, approximately 400 children aged 1 year and older die from SUDC annually. A major obstacle to studying these cases is that so-called molecular autopsies – which incorporate genetic analysis into the postmortem examination – typically do not assess the parents’ genetic information and thus limit the ability to identify de novo mutations, they added.

In a study published in the Proceedings of the National Academy of Sciences, Dr. Halvorsen’s group obtained whole exome sequence data from 124 “trios,” meaning a dead child and two living parents. They tested for excessive de novo mutations for different genes involved in conditions that included cardiac arrhythmias and epilepsy. The average age at the time of death for the children was 34.2 months; 54% were male, and 82% were White.

Children who died of SUDC were nearly 10 times as likely to have de novo mutations in genes associated with cardiac and seizure disorders as were unrelated healthy controls (odds ratio, 9.76). Most pathogenic variants were de novo, which highlights the importance of trio studies, the researchers noted.

The researchers identified 11 variants associated with increased risk of SUDC, 7 of which were de novo. Three of the 124 cases carried mutations (two for RYR2 and 1 for TNNI3) affecting genes in the CardiacEpilepsy dataset proposed by the American College of Medical Genetics and Genomics, strengthening the connection to seizure disorders.

Another notable finding was the identification of six de novo mutations involved in altering calcium-related regulation, which suggests a cardiac susceptibility to sudden death.

The data support “novel genetic causes of pediatric sudden deaths that could be discovered with larger cohorts,” the researchers noted. Taken together, they say, the gene mutations could play a role in approximately 9% of SUDC cases.

The study findings were limited by several factors, including lack of population-based case ascertainment, exclusive focus on unexplained deaths, potentially missed mutations, and use of DNA from blood as opposed to organs, the researchers noted.

However, they concluded, “the data indicate that deleterious de novo mutations are significant genetic risk factors for childhood sudden unexplained death, and that their identification may lead to medical intervention that ultimately saves lives.”

Findings highlight impact of SUDC

“This study is important because SUDC is a much more pressing medical need than most people realize,” said Richard Tsien, PhD, of New York University Langone Medical Center, and the corresponding author of the study.

Although SUDC is less common than SIDS, SUDC has essentially no targeted research funding, Dr. Tsien said. Study coauthor Laura Gould, MA, a researcher and mother who lost a young child to SUDC, worked with Orrin Devinsky, MD, to create a registry for families with cases of SUDC. This registry was instrumental in allowing the researchers to “do the molecular detective work we need to do” to see whether a genetic basis exists for SUDC, Dr. Tsien said.

“The detective work comes up with a consistent story,” he said. “More than half of the genes that we found are involved in the normal function of the heart and brain,” performing such functions as delivering calcium ions to the inside of the heart cells and nerve cells.

The study “is the first of its kind,” given the difficulty of acquiring DNA from the child and two parents in SUDC cases, Dr. Tsien said.

Overall, approximately 10% of the cases have a compelling explanation based on the coding of DNA, Dr. Tsien said. From a clinical standpoint, that information might affect what a clinician says to a parent.

A key takeaway is that most of the genetic mutations are spontaneous and are not inherited from the parents, Dr. Tsien said. The study findings indicate that parents who suffer an SUDC loss need not be discouraged from having children, he added.

For the long term, “the more we understand about these disorders, the more information we can offer to families,” he said. Eventually, clinicians might be able to use genetics to identify signs of when SUDC might be more likely. “For example, if a child shows a very mild seizure, this would alert them that there might be potential for a more drastic outcome.”

Meanwhile, families with SUDC cases may find support and benefit in signing up for the registry and knowing that other families have been through a similar experience, Dr. Tsien said.

Genetic studies create opportunities

A significant portion of pediatric mortality remains unexplained, according to Richard D. Goldstein, MD, of Boston Children’s Hospital. One reason is the lack of a formal diagnostic code to identify these deaths.

Research to date has suggested links between SUDC and a family history of febrile seizures, as well as differences in brain structure associated with epilepsy, Dr. Goldstein said.

“An important hypothesis is that these deaths are part of a continuum that also includes stillbirths, SIDS, and sudden unexpected death in epilepsy [SUDEP],” Dr. Goldstein said. “By mandate, investigations of these deaths occur under the jurisdiction of medical examiners and coroners and have, for the most part, been insulated from developments in modern medicine like genomics and proteomics, elements of what are referred to as the molecular autopsy, and studies such as the current study bring attention to what is being missed.”

Dr. Goldstein said the new study buttresses the “conventional clinical suspicion” about the likely causes of SUDC, “but also strengthens the association between sudden unexpected death in pediatrics (SUDP) and SUDEP that we and others have been positing. I think the researchers very nicely make the point that epilepsy and cardiac arrhythmia genes are not as separated in their effects as many would believe.”

As for the clinical applicability of the findings, Dr. Goldstein said medicine needs to offer parents more: “Pediatric deaths without explanation deserve more than a forensic investigation that concerns itself mostly with whether there has been foul play,” he said. “We need to figure out how to engage families, at an incredibly vulnerable time, in helping find the cause of the child’s death and also contributing to needed research. Most of the reported variants were de novo, which means that parent participation is needed to figure out these genetic factors but also that we can offer reassurance to families that other children are not at risk.”

The study was supported by the SUDC Foundation and Finding a Cure for Epilepsy and Seizures (New York University). Dr. Tsien disclosed support from the National Institutes of Health and a grant from FACES. Dr. Goldstein reported no relevant financial relationships.

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

In a large-scale study among Danish children, no statistically significant association was found between maternal hormonal contraception use and increased risk for central nervous system (CNS) tumors in their offspring.

The study was based on population-based registry data and included 1.1 million children age 19 or younger born in Denmark between 1996 and 2014.

The study, by Marie Hargreave, PhD, Danish Cancer Society Research Center, and colleagues, was published online Jan. 4 in the Journal of the American Medical Association.

Exposure to sex hormones in utero is a recognized cause of cancer in affected offspring, note the authors. Also, the incidence of CNS tumors, among the most common and lethal childhood cancer types, appears to be increasing. Hence, they sought to investigate if there may be a relationship between the two.

During a mean follow-up of 12.9 years, the team found that 725 children were diagnosed with a CNS tumor (47.2% female). Mean age at diagnosis was 7 years. The team noted that 11.5%, 65.7%, and 22.8% of diagnosed children were born to mothers with recent, previous, or no use of hormonal contraception, respectively.

The adjusted incidence rate of CNS tumors was 5.0 per 100,000 person-years for children born to mothers with recent hormonal contraception use (hazard ratio, 0.95), 4.5 per 100,000 person-years for children born to mothers with previous use (HR, 0.86), and 5.3 per 100,000 person-years for children born to mothers with no use.

While recent use of implants (HR, 0.9) and intrauterine devices (HR, 1.5) showed no statistically significant associations for the subgroups of nonoral progestin-only hormonal contraception assessed, the team found that progestin-only injections were significantly associated with an increased risk compared with no use (HR, 6.7). Also, in all post hoc sensitivity analyses, recent use of the main group of nonoral progestin-only products was significantly associated with CNS tumors.

The authors observe that an association between maternal use of injectable contraceptives and increased risk of chromosomal anomalies and major malformations in children has previously been reported. Those results for injections, however, were based on a small number of cases, the result of the likelihood test was null, and adjustments for multiple comparisons were not made. Even if the results for this subgroup are confirmed, the authors point out, because CNS tumors in children are uncommon, the high relative risk estimates would translate to low absolute risk increases.

Although the large number of person-years and cancers increases the statistical precision, and the population-based nationwide design increases the generalizability of the results, the authors caution that uncommonness of CNS tumors in children and the small number of cases in the studied cohort limit subgroup analyses and the statistical precision of certain estimates.

In an accompanying editorial, Logan G. Spector, PhD, and Christopher L. Moertel, MD, from the University of Minnesota Medical School, and H. Irene Su, MD, from the University of California, San Diego, echo the authors’ conclusions, and state: “Thus, women should be reassured about the use of hormonal contraception, including progestin-only injections, and the lack of any increased risk of CNS tumors in their offspring.”

The study was supported by the Danish Cancer Research Foundation, the Arvid Nilssons Foundation, the Gangsted Foundation, the Harboe Foundation, and the Johannes Clemmesens Foundation. Co-author Lina S. Mørch, PhD, reported receiving personal fees from Novo Nordisk as an employee from 2017 to 2019 and grants from Novo Nordisk for a collaborative research project outside the submitted work. Editorialist Christopher Moertel, MD, reported receiving personal fees from OX2 Therapeutics, a spin-off of the University of Minnesota that is involved in the development of brain tumor therapeutics.

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

In a large-scale study among Danish children, no statistically significant association was found between maternal hormonal contraception use and increased risk for central nervous system (CNS) tumors in their offspring.

The study was based on population-based registry data and included 1.1 million children age 19 or younger born in Denmark between 1996 and 2014.

The study, by Marie Hargreave, PhD, Danish Cancer Society Research Center, and colleagues, was published online Jan. 4 in the Journal of the American Medical Association.

Exposure to sex hormones in utero is a recognized cause of cancer in affected offspring, note the authors. Also, the incidence of CNS tumors, among the most common and lethal childhood cancer types, appears to be increasing. Hence, they sought to investigate if there may be a relationship between the two.

During a mean follow-up of 12.9 years, the team found that 725 children were diagnosed with a CNS tumor (47.2% female). Mean age at diagnosis was 7 years. The team noted that 11.5%, 65.7%, and 22.8% of diagnosed children were born to mothers with recent, previous, or no use of hormonal contraception, respectively.

The adjusted incidence rate of CNS tumors was 5.0 per 100,000 person-years for children born to mothers with recent hormonal contraception use (hazard ratio, 0.95), 4.5 per 100,000 person-years for children born to mothers with previous use (HR, 0.86), and 5.3 per 100,000 person-years for children born to mothers with no use.

While recent use of implants (HR, 0.9) and intrauterine devices (HR, 1.5) showed no statistically significant associations for the subgroups of nonoral progestin-only hormonal contraception assessed, the team found that progestin-only injections were significantly associated with an increased risk compared with no use (HR, 6.7). Also, in all post hoc sensitivity analyses, recent use of the main group of nonoral progestin-only products was significantly associated with CNS tumors.

The authors observe that an association between maternal use of injectable contraceptives and increased risk of chromosomal anomalies and major malformations in children has previously been reported. Those results for injections, however, were based on a small number of cases, the result of the likelihood test was null, and adjustments for multiple comparisons were not made. Even if the results for this subgroup are confirmed, the authors point out, because CNS tumors in children are uncommon, the high relative risk estimates would translate to low absolute risk increases.

Although the large number of person-years and cancers increases the statistical precision, and the population-based nationwide design increases the generalizability of the results, the authors caution that uncommonness of CNS tumors in children and the small number of cases in the studied cohort limit subgroup analyses and the statistical precision of certain estimates.

In an accompanying editorial, Logan G. Spector, PhD, and Christopher L. Moertel, MD, from the University of Minnesota Medical School, and H. Irene Su, MD, from the University of California, San Diego, echo the authors’ conclusions, and state: “Thus, women should be reassured about the use of hormonal contraception, including progestin-only injections, and the lack of any increased risk of CNS tumors in their offspring.”

The study was supported by the Danish Cancer Research Foundation, the Arvid Nilssons Foundation, the Gangsted Foundation, the Harboe Foundation, and the Johannes Clemmesens Foundation. Co-author Lina S. Mørch, PhD, reported receiving personal fees from Novo Nordisk as an employee from 2017 to 2019 and grants from Novo Nordisk for a collaborative research project outside the submitted work. Editorialist Christopher Moertel, MD, reported receiving personal fees from OX2 Therapeutics, a spin-off of the University of Minnesota that is involved in the development of brain tumor therapeutics.

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

In a large-scale study among Danish children, no statistically significant association was found between maternal hormonal contraception use and increased risk for central nervous system (CNS) tumors in their offspring.

The study was based on population-based registry data and included 1.1 million children age 19 or younger born in Denmark between 1996 and 2014.

The study, by Marie Hargreave, PhD, Danish Cancer Society Research Center, and colleagues, was published online Jan. 4 in the Journal of the American Medical Association.

Exposure to sex hormones in utero is a recognized cause of cancer in affected offspring, note the authors. Also, the incidence of CNS tumors, among the most common and lethal childhood cancer types, appears to be increasing. Hence, they sought to investigate if there may be a relationship between the two.

During a mean follow-up of 12.9 years, the team found that 725 children were diagnosed with a CNS tumor (47.2% female). Mean age at diagnosis was 7 years. The team noted that 11.5%, 65.7%, and 22.8% of diagnosed children were born to mothers with recent, previous, or no use of hormonal contraception, respectively.

The adjusted incidence rate of CNS tumors was 5.0 per 100,000 person-years for children born to mothers with recent hormonal contraception use (hazard ratio, 0.95), 4.5 per 100,000 person-years for children born to mothers with previous use (HR, 0.86), and 5.3 per 100,000 person-years for children born to mothers with no use.

While recent use of implants (HR, 0.9) and intrauterine devices (HR, 1.5) showed no statistically significant associations for the subgroups of nonoral progestin-only hormonal contraception assessed, the team found that progestin-only injections were significantly associated with an increased risk compared with no use (HR, 6.7). Also, in all post hoc sensitivity analyses, recent use of the main group of nonoral progestin-only products was significantly associated with CNS tumors.

The authors observe that an association between maternal use of injectable contraceptives and increased risk of chromosomal anomalies and major malformations in children has previously been reported. Those results for injections, however, were based on a small number of cases, the result of the likelihood test was null, and adjustments for multiple comparisons were not made. Even if the results for this subgroup are confirmed, the authors point out, because CNS tumors in children are uncommon, the high relative risk estimates would translate to low absolute risk increases.

Although the large number of person-years and cancers increases the statistical precision, and the population-based nationwide design increases the generalizability of the results, the authors caution that uncommonness of CNS tumors in children and the small number of cases in the studied cohort limit subgroup analyses and the statistical precision of certain estimates.

In an accompanying editorial, Logan G. Spector, PhD, and Christopher L. Moertel, MD, from the University of Minnesota Medical School, and H. Irene Su, MD, from the University of California, San Diego, echo the authors’ conclusions, and state: “Thus, women should be reassured about the use of hormonal contraception, including progestin-only injections, and the lack of any increased risk of CNS tumors in their offspring.”

The study was supported by the Danish Cancer Research Foundation, the Arvid Nilssons Foundation, the Gangsted Foundation, the Harboe Foundation, and the Johannes Clemmesens Foundation. Co-author Lina S. Mørch, PhD, reported receiving personal fees from Novo Nordisk as an employee from 2017 to 2019 and grants from Novo Nordisk for a collaborative research project outside the submitted work. Editorialist Christopher Moertel, MD, reported receiving personal fees from OX2 Therapeutics, a spin-off of the University of Minnesota that is involved in the development of brain tumor therapeutics.

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