The recent report from the SYNTAX trials should give pause to our interventionalist colleagues embarking on multiple angioplasty and stenting procedures in patients with complex coronary anatomy.

SYNTAX randomized 1,800 patients with left main or triple-vessel coronary artery disease to either percutaneous coronary intervention (PCI) with the TAXUS drug-eluting stent or coronary artery bypass grafting (CABG) after being judged by a heart team as being in equipoise in regard to the appropriateness of either procedure (Eur Heart J. 2011;32;2125-34). The findings of several previous analyses have trended toward benefit for CABG, but none as clearly as SYNTAX. The original study was reported 6 years ago (Lancet 2013 Feb;381:629-38) and indicated that CABG was superior to PCI in patients with complex lesions. The most recent 5-year data of that study (J Am Coll Cardiol. 2016 Jan:67;42-55) indicates that cardiac mortality in the CABG patients is superior to that in the PCI group (5.3% vs. 9.6%, respectively), and the follow-up data provide more in-depth analysis in addition to the mechanism of death. Most importantly, the recent 5-year data clarify the reasons PCI fails to measure up to the results of CABG in patients with complex coronary artery disease.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

The recent report from the SYNTAX trials should give pause to our interventionalist colleagues embarking on multiple angioplasty and stenting procedures in patients with complex coronary anatomy.

SYNTAX randomized 1,800 patients with left main or triple-vessel coronary artery disease to either percutaneous coronary intervention (PCI) with the TAXUS drug-eluting stent or coronary artery bypass grafting (CABG) after being judged by a heart team as being in equipoise in regard to the appropriateness of either procedure (Eur Heart J. 2011;32;2125-34). The findings of several previous analyses have trended toward benefit for CABG, but none as clearly as SYNTAX. The original study was reported 6 years ago (Lancet 2013 Feb;381:629-38) and indicated that CABG was superior to PCI in patients with complex lesions. The most recent 5-year data of that study (J Am Coll Cardiol. 2016 Jan:67;42-55) indicates that cardiac mortality in the CABG patients is superior to that in the PCI group (5.3% vs. 9.6%, respectively), and the follow-up data provide more in-depth analysis in addition to the mechanism of death. Most importantly, the recent 5-year data clarify the reasons PCI fails to measure up to the results of CABG in patients with complex coronary artery disease.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

The recent report from the SYNTAX trials should give pause to our interventionalist colleagues embarking on multiple angioplasty and stenting procedures in patients with complex coronary anatomy.

SYNTAX randomized 1,800 patients with left main or triple-vessel coronary artery disease to either percutaneous coronary intervention (PCI) with the TAXUS drug-eluting stent or coronary artery bypass grafting (CABG) after being judged by a heart team as being in equipoise in regard to the appropriateness of either procedure (Eur Heart J. 2011;32;2125-34). The findings of several previous analyses have trended toward benefit for CABG, but none as clearly as SYNTAX. The original study was reported 6 years ago (Lancet 2013 Feb;381:629-38) and indicated that CABG was superior to PCI in patients with complex lesions. The most recent 5-year data of that study (J Am Coll Cardiol. 2016 Jan:67;42-55) indicates that cardiac mortality in the CABG patients is superior to that in the PCI group (5.3% vs. 9.6%, respectively), and the follow-up data provide more in-depth analysis in addition to the mechanism of death. Most importantly, the recent 5-year data clarify the reasons PCI fails to measure up to the results of CABG in patients with complex coronary artery disease.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

NEW ORLEANS – Hypertensive patients without heart failure treated with the heart failure formulation sacubitril plus valsartan had a significantly greater drop in their left ventricular mass than did patients treated with olmesartan in a randomized trial with 114 patients.

Treatment with sacubitril plus valsartan for both 3 and 12 months led to roughly twice as much reduction in left ventricular (LV) mass as did treatment with olmesartan, and this difference persisted after adjustment for between-group differences in blood pressure reduction, Roland E. Schmieder, MD, reported at the American Heart Association Scientific Sessions.

Mitchel L. Zoler/Frontline Medical News

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

NEW ORLEANS – Hypertensive patients without heart failure treated with the heart failure formulation sacubitril plus valsartan had a significantly greater drop in their left ventricular mass than did patients treated with olmesartan in a randomized trial with 114 patients.

Treatment with sacubitril plus valsartan for both 3 and 12 months led to roughly twice as much reduction in left ventricular (LV) mass as did treatment with olmesartan, and this difference persisted after adjustment for between-group differences in blood pressure reduction, Roland E. Schmieder, MD, reported at the American Heart Association Scientific Sessions.

Mitchel L. Zoler/Frontline Medical News

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

NEW ORLEANS – Hypertensive patients without heart failure treated with the heart failure formulation sacubitril plus valsartan had a significantly greater drop in their left ventricular mass than did patients treated with olmesartan in a randomized trial with 114 patients.

Treatment with sacubitril plus valsartan for both 3 and 12 months led to roughly twice as much reduction in left ventricular (LV) mass as did treatment with olmesartan, and this difference persisted after adjustment for between-group differences in blood pressure reduction, Roland E. Schmieder, MD, reported at the American Heart Association Scientific Sessions.

Mitchel L. Zoler/Frontline Medical News

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

A new curricular “road map” attempts to lay out precisely what rheumatology fellows are expected to be able to know and do at different time points in their training.

The 80 “curricular milestones” for rheumatology, developed under the direction of the Accreditation Council for Graduate Medical Education, are meant to complement the 23 internal medicine subspecialty reporting milestones already mandated by the ACGME for use in trainee evaluation.

Unlike the reporting milestones, which came into use in 2014, the curricular milestones are not compulsory. Instead they “offer a guide so that trainees and the people teaching them know what’s expected of them,” said Lisa Criscione-Schreiber, MD, of Duke University, Durham, N.C., the lead author of a recent article in Arthritis Care & Research describing the new milestones (Arthritis Care Res. 2016 Nov 11. doi: 10.1002/acr.23151).

Shawn Rocco/Duke Health

A leap of faith?

Dr. Criscione-Schreiber, who is Duke’s rheumatology program director, acknowledged that the milestones’ value and utility remain to be determined. “We’re not sure it’s the best way, but it’s a try,” she said. “We’re all in an era of continuous quality improvement in which you change something then test whether it works. The ACGME is collecting data about all this – if they find out it’s burdensome, they have assured program directors that they will change it.”

Observation and feedback

A key goal of the milestones is to encourage direct observation of trainees. Dr. Panush and his colleagues, in their editorial, argue that “a wise and astute clinician educator ... can judge when trainees are ready to function independently and have learned how to keep learning and changing without needing menus of evaluations or detailed instruments.”

Dr. Criscione-Schreiber said there’s traditionally been less direct observation in rheumatology training than people would like to think. “It used to be more like what we call the piano analogy. You send them into a room for an hour alone with a piano and some sheet music and they come out saying ‘I can play the piano.’ And you believe them.”

Dr. Brown, meanwhile, compared traditional training approaches to what he called the teabag model. The trainee “was the teabag steeping in the hot water of an academic medical center, and the major criteria for finishing was time,” he said. “I think all of us would recognize that this doesn’t take into consideration different environments, different learning styles and rates of learning.”

Using the milestones

Dr. Panush, in an interview, noted that the implementation of rubric-based education in internal medicine training came with a host of problems resulting in published critiques. He cited a recent article by Ronald Witteles, MD, and Abraham Verghese, MD, both of Stanford (Calif.) University, that criticized the reporting milestones as onerous to implement in large internal medicine programs, leading to excess administrative work and box-ticking (JAMA Intern Med. 2016;176[11]:1599-1600).

But rheumatology fellowship programs, which are generally small, may be less likely to find the curricular milestones burdensome, their champions say. The success of these milestones depends, in large part, on how people choose to integrate them into their training programs.

“The milestones appear a little daunting because they’re new,” Dr. Bolster said, cautioning that they are not designed to be foisted wholesale on trainees. Used judiciously, she said, the curricular milestones can help identify areas of strength and weakness and foster dialogue. “What I do is select a few of them, a couple of times a year, to go over with each fellow,” she said. “I also recommend them for fellows to use as self-reflection, so that they may determine where they are in terms of training.”

Details vs. the big picture

Anne Bass, MD, the rheumatology program director at the Hospital for Special Surgery in New York, who did not take part in either the curricular milestones writing committee or the editorial, said they could be used piecemeal, helping program directors to design portions of their curriculum, or to provide feedback and remediation by pointing out areas of trainee weakness.

Training rheumatologists like pilots

The authors of the milestones say they’re responding to a sense widely shared in the rheumatology community that training must adapt to the needs of a changing field.

“Medicine is not the same as it was 10 or even 5 years ago, and certainly not as it was 20 years ago. A physician who is going to practice 10 years from now will require a different skill set,” Dr. Criscione-Schreiber said.

This, of course, includes many skills not directly related to patient care but rather successful functioning within current systems of health care delivery.

Dr. Criscione-Schreiber said that amid a coming shortage of rheumatologists, the next generation must be prepared to lead teams.

“We’re going to have clinics with nurses doing much of the education, and a whole team of people taking care of patients, if we have any hope of caring for the population in the U.S. that needs rheumatologists. It’s different from training a one-on-one doctor who sits in the room with a patient for 25 minutes,” she said.

Dr. Brown said he views the milestones effort, whether it proves successful or not, as an attempt to train in a way that ensures all future rheumatologists share the same core skills.

“People ask us all the time which doctor should they see for this or that condition, because they want to see someone really good,” Dr. Brown said. “Contrast that to the last time you got on an airplane. Did you ask a friend which pilot you should fly with? No, because you trusted that the pilot was competent, and had all requisite training, to safely pilot the plane. We want medicine to have many of those qualities and characteristics.”

Human beings are more complicated than airplanes, Dr. Brown acknowledged. “So it’s not perfectly analogous. But if we can more granularly describe training, and what it is we want to achieve, we’d all benefit – to the point where we can confidently tell you to see the rheumatologist trained in an accredited program who’s nearest your home.”

A new curricular “road map” attempts to lay out precisely what rheumatology fellows are expected to be able to know and do at different time points in their training.

The 80 “curricular milestones” for rheumatology, developed under the direction of the Accreditation Council for Graduate Medical Education, are meant to complement the 23 internal medicine subspecialty reporting milestones already mandated by the ACGME for use in trainee evaluation.

Unlike the reporting milestones, which came into use in 2014, the curricular milestones are not compulsory. Instead they “offer a guide so that trainees and the people teaching them know what’s expected of them,” said Lisa Criscione-Schreiber, MD, of Duke University, Durham, N.C., the lead author of a recent article in Arthritis Care & Research describing the new milestones (Arthritis Care Res. 2016 Nov 11. doi: 10.1002/acr.23151).

Shawn Rocco/Duke Health

A leap of faith?

Dr. Criscione-Schreiber, who is Duke’s rheumatology program director, acknowledged that the milestones’ value and utility remain to be determined. “We’re not sure it’s the best way, but it’s a try,” she said. “We’re all in an era of continuous quality improvement in which you change something then test whether it works. The ACGME is collecting data about all this – if they find out it’s burdensome, they have assured program directors that they will change it.”

Observation and feedback

A key goal of the milestones is to encourage direct observation of trainees. Dr. Panush and his colleagues, in their editorial, argue that “a wise and astute clinician educator ... can judge when trainees are ready to function independently and have learned how to keep learning and changing without needing menus of evaluations or detailed instruments.”

Dr. Criscione-Schreiber said there’s traditionally been less direct observation in rheumatology training than people would like to think. “It used to be more like what we call the piano analogy. You send them into a room for an hour alone with a piano and some sheet music and they come out saying ‘I can play the piano.’ And you believe them.”

Dr. Brown, meanwhile, compared traditional training approaches to what he called the teabag model. The trainee “was the teabag steeping in the hot water of an academic medical center, and the major criteria for finishing was time,” he said. “I think all of us would recognize that this doesn’t take into consideration different environments, different learning styles and rates of learning.”

Using the milestones

Dr. Panush, in an interview, noted that the implementation of rubric-based education in internal medicine training came with a host of problems resulting in published critiques. He cited a recent article by Ronald Witteles, MD, and Abraham Verghese, MD, both of Stanford (Calif.) University, that criticized the reporting milestones as onerous to implement in large internal medicine programs, leading to excess administrative work and box-ticking (JAMA Intern Med. 2016;176[11]:1599-1600).

But rheumatology fellowship programs, which are generally small, may be less likely to find the curricular milestones burdensome, their champions say. The success of these milestones depends, in large part, on how people choose to integrate them into their training programs.

“The milestones appear a little daunting because they’re new,” Dr. Bolster said, cautioning that they are not designed to be foisted wholesale on trainees. Used judiciously, she said, the curricular milestones can help identify areas of strength and weakness and foster dialogue. “What I do is select a few of them, a couple of times a year, to go over with each fellow,” she said. “I also recommend them for fellows to use as self-reflection, so that they may determine where they are in terms of training.”

Details vs. the big picture

Anne Bass, MD, the rheumatology program director at the Hospital for Special Surgery in New York, who did not take part in either the curricular milestones writing committee or the editorial, said they could be used piecemeal, helping program directors to design portions of their curriculum, or to provide feedback and remediation by pointing out areas of trainee weakness.

Training rheumatologists like pilots

The authors of the milestones say they’re responding to a sense widely shared in the rheumatology community that training must adapt to the needs of a changing field.

“Medicine is not the same as it was 10 or even 5 years ago, and certainly not as it was 20 years ago. A physician who is going to practice 10 years from now will require a different skill set,” Dr. Criscione-Schreiber said.

This, of course, includes many skills not directly related to patient care but rather successful functioning within current systems of health care delivery.

Dr. Criscione-Schreiber said that amid a coming shortage of rheumatologists, the next generation must be prepared to lead teams.

“We’re going to have clinics with nurses doing much of the education, and a whole team of people taking care of patients, if we have any hope of caring for the population in the U.S. that needs rheumatologists. It’s different from training a one-on-one doctor who sits in the room with a patient for 25 minutes,” she said.

Dr. Brown said he views the milestones effort, whether it proves successful or not, as an attempt to train in a way that ensures all future rheumatologists share the same core skills.

“People ask us all the time which doctor should they see for this or that condition, because they want to see someone really good,” Dr. Brown said. “Contrast that to the last time you got on an airplane. Did you ask a friend which pilot you should fly with? No, because you trusted that the pilot was competent, and had all requisite training, to safely pilot the plane. We want medicine to have many of those qualities and characteristics.”

Human beings are more complicated than airplanes, Dr. Brown acknowledged. “So it’s not perfectly analogous. But if we can more granularly describe training, and what it is we want to achieve, we’d all benefit – to the point where we can confidently tell you to see the rheumatologist trained in an accredited program who’s nearest your home.”

A new curricular “road map” attempts to lay out precisely what rheumatology fellows are expected to be able to know and do at different time points in their training.

The 80 “curricular milestones” for rheumatology, developed under the direction of the Accreditation Council for Graduate Medical Education, are meant to complement the 23 internal medicine subspecialty reporting milestones already mandated by the ACGME for use in trainee evaluation.

Unlike the reporting milestones, which came into use in 2014, the curricular milestones are not compulsory. Instead they “offer a guide so that trainees and the people teaching them know what’s expected of them,” said Lisa Criscione-Schreiber, MD, of Duke University, Durham, N.C., the lead author of a recent article in Arthritis Care & Research describing the new milestones (Arthritis Care Res. 2016 Nov 11. doi: 10.1002/acr.23151).

Shawn Rocco/Duke Health

A leap of faith?

Dr. Criscione-Schreiber, who is Duke’s rheumatology program director, acknowledged that the milestones’ value and utility remain to be determined. “We’re not sure it’s the best way, but it’s a try,” she said. “We’re all in an era of continuous quality improvement in which you change something then test whether it works. The ACGME is collecting data about all this – if they find out it’s burdensome, they have assured program directors that they will change it.”

Observation and feedback

A key goal of the milestones is to encourage direct observation of trainees. Dr. Panush and his colleagues, in their editorial, argue that “a wise and astute clinician educator ... can judge when trainees are ready to function independently and have learned how to keep learning and changing without needing menus of evaluations or detailed instruments.”

Dr. Criscione-Schreiber said there’s traditionally been less direct observation in rheumatology training than people would like to think. “It used to be more like what we call the piano analogy. You send them into a room for an hour alone with a piano and some sheet music and they come out saying ‘I can play the piano.’ And you believe them.”

Dr. Brown, meanwhile, compared traditional training approaches to what he called the teabag model. The trainee “was the teabag steeping in the hot water of an academic medical center, and the major criteria for finishing was time,” he said. “I think all of us would recognize that this doesn’t take into consideration different environments, different learning styles and rates of learning.”

Using the milestones

Dr. Panush, in an interview, noted that the implementation of rubric-based education in internal medicine training came with a host of problems resulting in published critiques. He cited a recent article by Ronald Witteles, MD, and Abraham Verghese, MD, both of Stanford (Calif.) University, that criticized the reporting milestones as onerous to implement in large internal medicine programs, leading to excess administrative work and box-ticking (JAMA Intern Med. 2016;176[11]:1599-1600).

But rheumatology fellowship programs, which are generally small, may be less likely to find the curricular milestones burdensome, their champions say. The success of these milestones depends, in large part, on how people choose to integrate them into their training programs.

“The milestones appear a little daunting because they’re new,” Dr. Bolster said, cautioning that they are not designed to be foisted wholesale on trainees. Used judiciously, she said, the curricular milestones can help identify areas of strength and weakness and foster dialogue. “What I do is select a few of them, a couple of times a year, to go over with each fellow,” she said. “I also recommend them for fellows to use as self-reflection, so that they may determine where they are in terms of training.”

Details vs. the big picture

Anne Bass, MD, the rheumatology program director at the Hospital for Special Surgery in New York, who did not take part in either the curricular milestones writing committee or the editorial, said they could be used piecemeal, helping program directors to design portions of their curriculum, or to provide feedback and remediation by pointing out areas of trainee weakness.

Training rheumatologists like pilots

The authors of the milestones say they’re responding to a sense widely shared in the rheumatology community that training must adapt to the needs of a changing field.

“Medicine is not the same as it was 10 or even 5 years ago, and certainly not as it was 20 years ago. A physician who is going to practice 10 years from now will require a different skill set,” Dr. Criscione-Schreiber said.

This, of course, includes many skills not directly related to patient care but rather successful functioning within current systems of health care delivery.

Dr. Criscione-Schreiber said that amid a coming shortage of rheumatologists, the next generation must be prepared to lead teams.

“We’re going to have clinics with nurses doing much of the education, and a whole team of people taking care of patients, if we have any hope of caring for the population in the U.S. that needs rheumatologists. It’s different from training a one-on-one doctor who sits in the room with a patient for 25 minutes,” she said.

Dr. Brown said he views the milestones effort, whether it proves successful or not, as an attempt to train in a way that ensures all future rheumatologists share the same core skills.

“People ask us all the time which doctor should they see for this or that condition, because they want to see someone really good,” Dr. Brown said. “Contrast that to the last time you got on an airplane. Did you ask a friend which pilot you should fly with? No, because you trusted that the pilot was competent, and had all requisite training, to safely pilot the plane. We want medicine to have many of those qualities and characteristics.”

Human beings are more complicated than airplanes, Dr. Brown acknowledged. “So it’s not perfectly analogous. But if we can more granularly describe training, and what it is we want to achieve, we’d all benefit – to the point where we can confidently tell you to see the rheumatologist trained in an accredited program who’s nearest your home.”

A while ago, I gave a talk on LGBT health to a group of primary care pediatricians. Although I was glad that they invited me to speak, I also sensed some discomfort in the audience. At the end of the lecture, many pediatricians told me that they were uncomfortable with bringing up the topic of sexuality and gender identity with their patients, and others wanted guidance on how to ask questions on sexuality and gender identity.

There are many barriers for primary pediatricians in addressing sexuality and gender identity concerns in their patients. First, pediatricians often will have up to 15 minutes for a visit, so they will have little time to address a complex issue. Second, primary care pediatricians may have known many of their patients since birth, and asking questions on sexuality and gender can feel awkward. Finally, many pediatricians may be working in more conservative areas in the country where asking questions on sexuality and gender identity may be controversial.

Tip No. 1: The environment counts

I cannot overstate how important it is to make your clinic a welcoming place for LGBT youth. Having various signs and stickers – like rainbow flags or the Human Rights Campaign sticker – will signal to LGBT youth that they are safe in your clinic. Creating a safe and welcoming environment is important because many people in the LGBT community have experienced rejection and discrimination from their primary care doctors.¹ Making your clinic a safe space will make it easier and efficient for patients to ask questions about sexuality and gender identity (see Dr. Gaya Chelvakumar’s column “Creating safe spaces for LGBTQ youth, families in health care settings” at pediatricnews.com).

Tip No. 2: Consider the context

Most likely, many presenting complaints – such as colds or sports injuries – of your adolescent patients will not involve sexual orientation or gender identity. There are exceptions. If you suspect an STD, then the risk for certain infections, such as HIV² or gonorrhea of the anus or of the pharynx³ are higher in gay young men. For the latter, your screening method would be different (that is, obtaining a pharyngeal swab or an anal swab instead of a urine sample). Also, because many LGBT youth have higher rates of mental health problems compared with heterosexual youth,⁴ you may want to ask questions about sexuality or gender identity to patients complaining of depressive or anxiety symptoms. This is especially important for transgender youth, because the implementation of pubertal blockers or cross-sex hormones can be therapeutic.⁵ To prevent or reduce many of these health problems, asking about sexuality and gender identity is a good idea during the well visit, when you may have more time.

Tip No. 3: Not all developmental stages are considered equal

Adolescence is a period of rapid and phasic growth. Formation of an identity is one of the major psychosocial tasks for adolescence,⁶ and sexuality and gender are important identities. In general, in early adolescence identity becomes an issue as the teenager gains autonomy from parents. I typically start asking questions about sexuality and gender when the patient is 11 or 12, because many children may not understand sexuality and gender identity at a younger age. At these ages, I ask these questions with the parents in the room, then I ask them confidentially on subsequent well visits. This approach serves two purposes: it will prepare the adolescent for these complex and thought-provoking questions in future encounters, and it gives the parents an idea of the type of questions you will ask the children when they are old enough for the confidential visit, helping parents feel more comfortable in stepping out of the room during this time.

Tip No. 4: Keep it confidential

Many adolescents are reluctant to see a doctor, even if they are sick. The primary reason adolescents do not seek care is the fear that the provider will tell their parents about their illness.⁷ Although this should be applicable to all of your adolescent patients, you should make an extra effort to explicitly state to LGBT patients that the clinic visit is confidential (with the exception of risk of suicide, homicide, or child abuse). This is important for LGBT youth who are not out to their parents and may be in danger if they do come out.⁸

Tip No. 5: Normalize, normalize, normalize

Because of the stigma and discrimination surrounding sexual orientation and gender identity, many LGBT youth will be reluctant to disclose their sexual orientation or gender identity to their health care providers. At the same time, heterosexual youth may think that you’re asking them questions about sexuality or gender identity because you suspect them to be a member of the LGBT community. To avoid this awkward situation, many pediatricians do not ask these questions at all. A good remedy for this is to preface your questions about sexual orientation or gender identity by saying that you ask these questions to all your patients – that way no one feels singled out.

Tip No. 6: Ask for permission

As previously mentioned, members of the LGBT community may experience discrimination from their health care providers after disclosing to them their sexual orientation or gender identity.¹ This rejection can be traumatizing for LGBT youth, making them reluctant to discuss any issues related to sexual orientation or gender identity with any medical provider. As part of the trauma-informed approach, asking for permission before delving into issues related to sexual orientation and gender identity will give LGBT patients a sense of control, especially in an environment where there is a significant power differential.

Tip No. 7: Treat this as a skill

Despite the pressures for primary care pediatricians to maintain an efficient and effective clinical practice, many strive to learn new skills to provide the best care for their patients. Asking questions about sexuality and gender identity should be one of those skills. As with any skill, it will feel unnatural at first, and it will require practice. Mastering this skill, however, will help you address the health needs of this vulnerable population.

Asking questions about sexuality and gender identity is difficult for the primary care pediatrician. Hopefully, these tips can help you develop this important skill. It will also help you reach out to a population that is wary of the health care system.

References

1. J Am Board Fam Med. 2016;29(1):156-60.

2. https://www.cdc.gov/hiv/group/msm/index.html.

3. https://www.cdc.gov/std/tg2015/default.htm.

4. J Adolesc Health. 2011;49(2):115-23.

5. Nat Rev Endocrinol. 2011;7(8):466-72.
6. Neinstein LS. Adolescent health care: a practical guide. 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2008.

7. J Adolesc Health. 2007;40(3):218-26.

8. Am J Orthopsychiatry. 1998;68(3):361-71.

Dr. Montano is an adolescent medicine fellow at Children’s Hospital of Pittsburgh of the University of Pittsburgh Medical Center and a postdoctoral fellow in the department of pediatrics at the University of Pittsburgh. Email him at pdnews@frontlinemedcom.com.

A while ago, I gave a talk on LGBT health to a group of primary care pediatricians. Although I was glad that they invited me to speak, I also sensed some discomfort in the audience. At the end of the lecture, many pediatricians told me that they were uncomfortable with bringing up the topic of sexuality and gender identity with their patients, and others wanted guidance on how to ask questions on sexuality and gender identity.

There are many barriers for primary pediatricians in addressing sexuality and gender identity concerns in their patients. First, pediatricians often will have up to 15 minutes for a visit, so they will have little time to address a complex issue. Second, primary care pediatricians may have known many of their patients since birth, and asking questions on sexuality and gender can feel awkward. Finally, many pediatricians may be working in more conservative areas in the country where asking questions on sexuality and gender identity may be controversial.

Tip No. 1: The environment counts

I cannot overstate how important it is to make your clinic a welcoming place for LGBT youth. Having various signs and stickers – like rainbow flags or the Human Rights Campaign sticker – will signal to LGBT youth that they are safe in your clinic. Creating a safe and welcoming environment is important because many people in the LGBT community have experienced rejection and discrimination from their primary care doctors.¹ Making your clinic a safe space will make it easier and efficient for patients to ask questions about sexuality and gender identity (see Dr. Gaya Chelvakumar’s column “Creating safe spaces for LGBTQ youth, families in health care settings” at pediatricnews.com).

Tip No. 2: Consider the context

Most likely, many presenting complaints – such as colds or sports injuries – of your adolescent patients will not involve sexual orientation or gender identity. There are exceptions. If you suspect an STD, then the risk for certain infections, such as HIV² or gonorrhea of the anus or of the pharynx³ are higher in gay young men. For the latter, your screening method would be different (that is, obtaining a pharyngeal swab or an anal swab instead of a urine sample). Also, because many LGBT youth have higher rates of mental health problems compared with heterosexual youth,⁴ you may want to ask questions about sexuality or gender identity to patients complaining of depressive or anxiety symptoms. This is especially important for transgender youth, because the implementation of pubertal blockers or cross-sex hormones can be therapeutic.⁵ To prevent or reduce many of these health problems, asking about sexuality and gender identity is a good idea during the well visit, when you may have more time.

Tip No. 3: Not all developmental stages are considered equal

Adolescence is a period of rapid and phasic growth. Formation of an identity is one of the major psychosocial tasks for adolescence,⁶ and sexuality and gender are important identities. In general, in early adolescence identity becomes an issue as the teenager gains autonomy from parents. I typically start asking questions about sexuality and gender when the patient is 11 or 12, because many children may not understand sexuality and gender identity at a younger age. At these ages, I ask these questions with the parents in the room, then I ask them confidentially on subsequent well visits. This approach serves two purposes: it will prepare the adolescent for these complex and thought-provoking questions in future encounters, and it gives the parents an idea of the type of questions you will ask the children when they are old enough for the confidential visit, helping parents feel more comfortable in stepping out of the room during this time.

Tip No. 4: Keep it confidential

Many adolescents are reluctant to see a doctor, even if they are sick. The primary reason adolescents do not seek care is the fear that the provider will tell their parents about their illness.⁷ Although this should be applicable to all of your adolescent patients, you should make an extra effort to explicitly state to LGBT patients that the clinic visit is confidential (with the exception of risk of suicide, homicide, or child abuse). This is important for LGBT youth who are not out to their parents and may be in danger if they do come out.⁸

Tip No. 5: Normalize, normalize, normalize

Because of the stigma and discrimination surrounding sexual orientation and gender identity, many LGBT youth will be reluctant to disclose their sexual orientation or gender identity to their health care providers. At the same time, heterosexual youth may think that you’re asking them questions about sexuality or gender identity because you suspect them to be a member of the LGBT community. To avoid this awkward situation, many pediatricians do not ask these questions at all. A good remedy for this is to preface your questions about sexual orientation or gender identity by saying that you ask these questions to all your patients – that way no one feels singled out.

Tip No. 6: Ask for permission

As previously mentioned, members of the LGBT community may experience discrimination from their health care providers after disclosing to them their sexual orientation or gender identity.¹ This rejection can be traumatizing for LGBT youth, making them reluctant to discuss any issues related to sexual orientation or gender identity with any medical provider. As part of the trauma-informed approach, asking for permission before delving into issues related to sexual orientation and gender identity will give LGBT patients a sense of control, especially in an environment where there is a significant power differential.

Tip No. 7: Treat this as a skill

Despite the pressures for primary care pediatricians to maintain an efficient and effective clinical practice, many strive to learn new skills to provide the best care for their patients. Asking questions about sexuality and gender identity should be one of those skills. As with any skill, it will feel unnatural at first, and it will require practice. Mastering this skill, however, will help you address the health needs of this vulnerable population.

Asking questions about sexuality and gender identity is difficult for the primary care pediatrician. Hopefully, these tips can help you develop this important skill. It will also help you reach out to a population that is wary of the health care system.

References

1. J Am Board Fam Med. 2016;29(1):156-60.

2. https://www.cdc.gov/hiv/group/msm/index.html.

3. https://www.cdc.gov/std/tg2015/default.htm.

4. J Adolesc Health. 2011;49(2):115-23.

5. Nat Rev Endocrinol. 2011;7(8):466-72.
6. Neinstein LS. Adolescent health care: a practical guide. 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2008.

7. J Adolesc Health. 2007;40(3):218-26.

8. Am J Orthopsychiatry. 1998;68(3):361-71.

Dr. Montano is an adolescent medicine fellow at Children’s Hospital of Pittsburgh of the University of Pittsburgh Medical Center and a postdoctoral fellow in the department of pediatrics at the University of Pittsburgh. Email him at pdnews@frontlinemedcom.com.

A while ago, I gave a talk on LGBT health to a group of primary care pediatricians. Although I was glad that they invited me to speak, I also sensed some discomfort in the audience. At the end of the lecture, many pediatricians told me that they were uncomfortable with bringing up the topic of sexuality and gender identity with their patients, and others wanted guidance on how to ask questions on sexuality and gender identity.

There are many barriers for primary pediatricians in addressing sexuality and gender identity concerns in their patients. First, pediatricians often will have up to 15 minutes for a visit, so they will have little time to address a complex issue. Second, primary care pediatricians may have known many of their patients since birth, and asking questions on sexuality and gender can feel awkward. Finally, many pediatricians may be working in more conservative areas in the country where asking questions on sexuality and gender identity may be controversial.

Tip No. 1: The environment counts

I cannot overstate how important it is to make your clinic a welcoming place for LGBT youth. Having various signs and stickers – like rainbow flags or the Human Rights Campaign sticker – will signal to LGBT youth that they are safe in your clinic. Creating a safe and welcoming environment is important because many people in the LGBT community have experienced rejection and discrimination from their primary care doctors.¹ Making your clinic a safe space will make it easier and efficient for patients to ask questions about sexuality and gender identity (see Dr. Gaya Chelvakumar’s column “Creating safe spaces for LGBTQ youth, families in health care settings” at pediatricnews.com).

Tip No. 2: Consider the context

Most likely, many presenting complaints – such as colds or sports injuries – of your adolescent patients will not involve sexual orientation or gender identity. There are exceptions. If you suspect an STD, then the risk for certain infections, such as HIV² or gonorrhea of the anus or of the pharynx³ are higher in gay young men. For the latter, your screening method would be different (that is, obtaining a pharyngeal swab or an anal swab instead of a urine sample). Also, because many LGBT youth have higher rates of mental health problems compared with heterosexual youth,⁴ you may want to ask questions about sexuality or gender identity to patients complaining of depressive or anxiety symptoms. This is especially important for transgender youth, because the implementation of pubertal blockers or cross-sex hormones can be therapeutic.⁵ To prevent or reduce many of these health problems, asking about sexuality and gender identity is a good idea during the well visit, when you may have more time.

Tip No. 3: Not all developmental stages are considered equal

Adolescence is a period of rapid and phasic growth. Formation of an identity is one of the major psychosocial tasks for adolescence,⁶ and sexuality and gender are important identities. In general, in early adolescence identity becomes an issue as the teenager gains autonomy from parents. I typically start asking questions about sexuality and gender when the patient is 11 or 12, because many children may not understand sexuality and gender identity at a younger age. At these ages, I ask these questions with the parents in the room, then I ask them confidentially on subsequent well visits. This approach serves two purposes: it will prepare the adolescent for these complex and thought-provoking questions in future encounters, and it gives the parents an idea of the type of questions you will ask the children when they are old enough for the confidential visit, helping parents feel more comfortable in stepping out of the room during this time.

Tip No. 4: Keep it confidential

Many adolescents are reluctant to see a doctor, even if they are sick. The primary reason adolescents do not seek care is the fear that the provider will tell their parents about their illness.⁷ Although this should be applicable to all of your adolescent patients, you should make an extra effort to explicitly state to LGBT patients that the clinic visit is confidential (with the exception of risk of suicide, homicide, or child abuse). This is important for LGBT youth who are not out to their parents and may be in danger if they do come out.⁸

Tip No. 5: Normalize, normalize, normalize

Because of the stigma and discrimination surrounding sexual orientation and gender identity, many LGBT youth will be reluctant to disclose their sexual orientation or gender identity to their health care providers. At the same time, heterosexual youth may think that you’re asking them questions about sexuality or gender identity because you suspect them to be a member of the LGBT community. To avoid this awkward situation, many pediatricians do not ask these questions at all. A good remedy for this is to preface your questions about sexual orientation or gender identity by saying that you ask these questions to all your patients – that way no one feels singled out.

Tip No. 6: Ask for permission

As previously mentioned, members of the LGBT community may experience discrimination from their health care providers after disclosing to them their sexual orientation or gender identity.¹ This rejection can be traumatizing for LGBT youth, making them reluctant to discuss any issues related to sexual orientation or gender identity with any medical provider. As part of the trauma-informed approach, asking for permission before delving into issues related to sexual orientation and gender identity will give LGBT patients a sense of control, especially in an environment where there is a significant power differential.

Tip No. 7: Treat this as a skill

Despite the pressures for primary care pediatricians to maintain an efficient and effective clinical practice, many strive to learn new skills to provide the best care for their patients. Asking questions about sexuality and gender identity should be one of those skills. As with any skill, it will feel unnatural at first, and it will require practice. Mastering this skill, however, will help you address the health needs of this vulnerable population.

Asking questions about sexuality and gender identity is difficult for the primary care pediatrician. Hopefully, these tips can help you develop this important skill. It will also help you reach out to a population that is wary of the health care system.

References

1. J Am Board Fam Med. 2016;29(1):156-60.

2. https://www.cdc.gov/hiv/group/msm/index.html.

3. https://www.cdc.gov/std/tg2015/default.htm.

4. J Adolesc Health. 2011;49(2):115-23.

5. Nat Rev Endocrinol. 2011;7(8):466-72.
6. Neinstein LS. Adolescent health care: a practical guide. 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2008.

7. J Adolesc Health. 2007;40(3):218-26.

8. Am J Orthopsychiatry. 1998;68(3):361-71.

Dr. Montano is an adolescent medicine fellow at Children’s Hospital of Pittsburgh of the University of Pittsburgh Medical Center and a postdoctoral fellow in the department of pediatrics at the University of Pittsburgh. Email him at pdnews@frontlinemedcom.com.

Contents

Opioid-Sparing Pain Control in Outpatient Total Joint Arthroplasty

John W. Barrington, MD

Addressing the Opioid Epidemic With Multimodal Pain Management

Michael A. Kelly, MD

Comprehensive Care for Joint Replacement (CJR) Bundle Expense in Perioperative Pain Management

Susan D. Bear, PharmD, BCPS

The Role of Liposomal Bupivacaine in Value-Based Care

Richard Iorio, MD

Click here to read the supplement

Contents

Opioid-Sparing Pain Control in Outpatient Total Joint Arthroplasty

John W. Barrington, MD

Addressing the Opioid Epidemic With Multimodal Pain Management

Michael A. Kelly, MD

Comprehensive Care for Joint Replacement (CJR) Bundle Expense in Perioperative Pain Management

Susan D. Bear, PharmD, BCPS

The Role of Liposomal Bupivacaine in Value-Based Care

Richard Iorio, MD

Click here to read the supplement

Contents

Opioid-Sparing Pain Control in Outpatient Total Joint Arthroplasty

John W. Barrington, MD

Addressing the Opioid Epidemic With Multimodal Pain Management

Michael A. Kelly, MD

Comprehensive Care for Joint Replacement (CJR) Bundle Expense in Perioperative Pain Management

Susan D. Bear, PharmD, BCPS

The Role of Liposomal Bupivacaine in Value-Based Care

Richard Iorio, MD

Click here to read the supplement

Oral pomalidomide, a derivative of thalidomide with immunomodulatory, antiangiogenic, and antiproliferative properties, proved to be well tolerated and effective against Kaposi’s sarcoma (KS) in a small phase I/II study, investigators reported in the Journal of Clinical Oncology.

There is a substantial need for oral therapies for KS, which often recurs and requires treatment, at least intermittently, for years. Existing treatments are cytotoxic agents, such as anthracyclines that are poorly tolerated and unsuitable for long-term use, said Mark N. Polizzotto, MD, of the National Cancer Institute, Bethesda, Md., and his associates.

They examined the tolerability and efficacy of pomalidomide against KS in a single-center, open-label trial involving 21 men and 1 transgender woman who had at least five evaluable cutaneous lesions. Fifteen of these participants had HIV infection. All of the patients were heavily pretreated with antiretrovirals and other agents, including thalidomide or lenalidomide, and most (17) had advanced KS with tumor-associated edema. The study participants received 5-mg oral pomalidomide once daily for 21 days in 28-day cycles for up to 12 cycles.

Sixteen patients showed an objective tumor response (overall response rate, 73%), including four who achieved a complete response (ORR, 18%). All 7 of the participants who didn’t have HIV showed an objective tumor response (ORR, 100%), as did 9 of the 15 HIV-infected participants (ORR, 60%). Three more participants, including one who was nonadeherent and lost to follow-up, achieved a partial tumor response.

Tumor responses included a decrease in the number of lesions and a decrease in the number of nodular lesions, as well as complete flattening of lesions, resolution of edema, and improvement in appearance. “The latter is particularly important because visible KS is a major source of stigma,” Dr. Polizzotto and his associates said (J Clin Oncol. 2016 Oct 3;34[34]:4125-32).

Two patients reported substantial subjective improvement in foot pain and appearance; one said he was pleased to be able to resume wearing closed shoes, the investigators noted. Treatment response generally was rapid, often commencing before the first follow-up at 4 weeks.

Pomalidomide was generally well tolerated. Adverse effects were frequent but mild and self-limiting, and they included neutropenia, constipation, anemia, fatigue, and rash. No patients required hospitalization, and there were no thromboembolic events. Three study participants developed malignancies after treatment: an Epstein-Barr-virus–associated Hodgkin lymphoma 1 year after the trial, a primary effusion lymphoma 15 months after, and a squamous-cell skin carcinoma. These probably reflect the patients’ underlying immunodeficiency, but the possibility that pomalidomide could contribute to malignancies in this high-risk population should be carefully explored in future studies, the investigators said.

“In resource-rich regions, pomalidomide may be of particular use in HIV-uninfected patients, in patients who have received substantial cumulative doses of anthracyclines, and in patients with less extensive but symptomatic disease for whom avoidance of cytotoxic chemotherapy would be beneficial. In resource-limited regions, there is an urgent need for effective and tolerable oral agents; with appropriate safeguards and monitoring, pomalidomide could address this,” Dr. Polizzotto and his associates wrote.

“Confirmatory studies of pomalidomide, alone and in combination with cytotoxic chemotherapy, are planned, including in sub-Saharan Africa,” they added.

op@frontlinemedcom.com

Oral pomalidomide, a derivative of thalidomide with immunomodulatory, antiangiogenic, and antiproliferative properties, proved to be well tolerated and effective against Kaposi’s sarcoma (KS) in a small phase I/II study, investigators reported in the Journal of Clinical Oncology.

There is a substantial need for oral therapies for KS, which often recurs and requires treatment, at least intermittently, for years. Existing treatments are cytotoxic agents, such as anthracyclines that are poorly tolerated and unsuitable for long-term use, said Mark N. Polizzotto, MD, of the National Cancer Institute, Bethesda, Md., and his associates.

They examined the tolerability and efficacy of pomalidomide against KS in a single-center, open-label trial involving 21 men and 1 transgender woman who had at least five evaluable cutaneous lesions. Fifteen of these participants had HIV infection. All of the patients were heavily pretreated with antiretrovirals and other agents, including thalidomide or lenalidomide, and most (17) had advanced KS with tumor-associated edema. The study participants received 5-mg oral pomalidomide once daily for 21 days in 28-day cycles for up to 12 cycles.

Sixteen patients showed an objective tumor response (overall response rate, 73%), including four who achieved a complete response (ORR, 18%). All 7 of the participants who didn’t have HIV showed an objective tumor response (ORR, 100%), as did 9 of the 15 HIV-infected participants (ORR, 60%). Three more participants, including one who was nonadeherent and lost to follow-up, achieved a partial tumor response.

Tumor responses included a decrease in the number of lesions and a decrease in the number of nodular lesions, as well as complete flattening of lesions, resolution of edema, and improvement in appearance. “The latter is particularly important because visible KS is a major source of stigma,” Dr. Polizzotto and his associates said (J Clin Oncol. 2016 Oct 3;34[34]:4125-32).

Two patients reported substantial subjective improvement in foot pain and appearance; one said he was pleased to be able to resume wearing closed shoes, the investigators noted. Treatment response generally was rapid, often commencing before the first follow-up at 4 weeks.

Pomalidomide was generally well tolerated. Adverse effects were frequent but mild and self-limiting, and they included neutropenia, constipation, anemia, fatigue, and rash. No patients required hospitalization, and there were no thromboembolic events. Three study participants developed malignancies after treatment: an Epstein-Barr-virus–associated Hodgkin lymphoma 1 year after the trial, a primary effusion lymphoma 15 months after, and a squamous-cell skin carcinoma. These probably reflect the patients’ underlying immunodeficiency, but the possibility that pomalidomide could contribute to malignancies in this high-risk population should be carefully explored in future studies, the investigators said.

“In resource-rich regions, pomalidomide may be of particular use in HIV-uninfected patients, in patients who have received substantial cumulative doses of anthracyclines, and in patients with less extensive but symptomatic disease for whom avoidance of cytotoxic chemotherapy would be beneficial. In resource-limited regions, there is an urgent need for effective and tolerable oral agents; with appropriate safeguards and monitoring, pomalidomide could address this,” Dr. Polizzotto and his associates wrote.

“Confirmatory studies of pomalidomide, alone and in combination with cytotoxic chemotherapy, are planned, including in sub-Saharan Africa,” they added.

op@frontlinemedcom.com

Oral pomalidomide, a derivative of thalidomide with immunomodulatory, antiangiogenic, and antiproliferative properties, proved to be well tolerated and effective against Kaposi’s sarcoma (KS) in a small phase I/II study, investigators reported in the Journal of Clinical Oncology.

There is a substantial need for oral therapies for KS, which often recurs and requires treatment, at least intermittently, for years. Existing treatments are cytotoxic agents, such as anthracyclines that are poorly tolerated and unsuitable for long-term use, said Mark N. Polizzotto, MD, of the National Cancer Institute, Bethesda, Md., and his associates.

They examined the tolerability and efficacy of pomalidomide against KS in a single-center, open-label trial involving 21 men and 1 transgender woman who had at least five evaluable cutaneous lesions. Fifteen of these participants had HIV infection. All of the patients were heavily pretreated with antiretrovirals and other agents, including thalidomide or lenalidomide, and most (17) had advanced KS with tumor-associated edema. The study participants received 5-mg oral pomalidomide once daily for 21 days in 28-day cycles for up to 12 cycles.

Sixteen patients showed an objective tumor response (overall response rate, 73%), including four who achieved a complete response (ORR, 18%). All 7 of the participants who didn’t have HIV showed an objective tumor response (ORR, 100%), as did 9 of the 15 HIV-infected participants (ORR, 60%). Three more participants, including one who was nonadeherent and lost to follow-up, achieved a partial tumor response.

Tumor responses included a decrease in the number of lesions and a decrease in the number of nodular lesions, as well as complete flattening of lesions, resolution of edema, and improvement in appearance. “The latter is particularly important because visible KS is a major source of stigma,” Dr. Polizzotto and his associates said (J Clin Oncol. 2016 Oct 3;34[34]:4125-32).

Two patients reported substantial subjective improvement in foot pain and appearance; one said he was pleased to be able to resume wearing closed shoes, the investigators noted. Treatment response generally was rapid, often commencing before the first follow-up at 4 weeks.

Pomalidomide was generally well tolerated. Adverse effects were frequent but mild and self-limiting, and they included neutropenia, constipation, anemia, fatigue, and rash. No patients required hospitalization, and there were no thromboembolic events. Three study participants developed malignancies after treatment: an Epstein-Barr-virus–associated Hodgkin lymphoma 1 year after the trial, a primary effusion lymphoma 15 months after, and a squamous-cell skin carcinoma. These probably reflect the patients’ underlying immunodeficiency, but the possibility that pomalidomide could contribute to malignancies in this high-risk population should be carefully explored in future studies, the investigators said.

“In resource-rich regions, pomalidomide may be of particular use in HIV-uninfected patients, in patients who have received substantial cumulative doses of anthracyclines, and in patients with less extensive but symptomatic disease for whom avoidance of cytotoxic chemotherapy would be beneficial. In resource-limited regions, there is an urgent need for effective and tolerable oral agents; with appropriate safeguards and monitoring, pomalidomide could address this,” Dr. Polizzotto and his associates wrote.

“Confirmatory studies of pomalidomide, alone and in combination with cytotoxic chemotherapy, are planned, including in sub-Saharan Africa,” they added.

op@frontlinemedcom.com

SAN ANTONIO – Every day, practicing oncologists sort through mountains of data from treatment guidelines, clinical trials, protocols, and algorithms to make the best possible therapeutic decisions for their patients.

At Manipal Hospitals in Bangalore, India, those decisions are informed with the aid of Watson for Oncology (WFO), a software platform developed by IBM in concert with clinicians and investigators at Memorial Sloan Kettering Cancer Center in New York City.

In this video interview at the San Antonio Breast Cancer Symposium, S.P. Somashekhar, MBBS, MS, MCH, chairman of the Manipal Comprehensive Cancer Center, discusses how the system is used by the members of the center’s multidisciplinary tumor board to inform decision making. He also describes results of a study he presented at the symposium that shows a relatively high degree of concordance between clinician and WFO choices in the treatment of patients with local breast cancer but less agreement when it comes to the management of metastatic disease, for which there is no universal standard of care.

SAN ANTONIO – Every day, practicing oncologists sort through mountains of data from treatment guidelines, clinical trials, protocols, and algorithms to make the best possible therapeutic decisions for their patients.

At Manipal Hospitals in Bangalore, India, those decisions are informed with the aid of Watson for Oncology (WFO), a software platform developed by IBM in concert with clinicians and investigators at Memorial Sloan Kettering Cancer Center in New York City.

In this video interview at the San Antonio Breast Cancer Symposium, S.P. Somashekhar, MBBS, MS, MCH, chairman of the Manipal Comprehensive Cancer Center, discusses how the system is used by the members of the center’s multidisciplinary tumor board to inform decision making. He also describes results of a study he presented at the symposium that shows a relatively high degree of concordance between clinician and WFO choices in the treatment of patients with local breast cancer but less agreement when it comes to the management of metastatic disease, for which there is no universal standard of care.

SAN ANTONIO – Every day, practicing oncologists sort through mountains of data from treatment guidelines, clinical trials, protocols, and algorithms to make the best possible therapeutic decisions for their patients.

At Manipal Hospitals in Bangalore, India, those decisions are informed with the aid of Watson for Oncology (WFO), a software platform developed by IBM in concert with clinicians and investigators at Memorial Sloan Kettering Cancer Center in New York City.

In this video interview at the San Antonio Breast Cancer Symposium, S.P. Somashekhar, MBBS, MS, MCH, chairman of the Manipal Comprehensive Cancer Center, discusses how the system is used by the members of the center’s multidisciplinary tumor board to inform decision making. He also describes results of a study he presented at the symposium that shows a relatively high degree of concordance between clinician and WFO choices in the treatment of patients with local breast cancer but less agreement when it comes to the management of metastatic disease, for which there is no universal standard of care.

Secondary complex regional pain syndrome is significantly more likely in people currently experiencing CRPS in an unrelated extremity than in the general population, according to Ellen Satteson, MD, and her associates.

In a study of 93 patients with CRPS, 20.4% developed secondary CRPS in another extremity. Twenty patients in the primary CRPS group experienced a secondary inciting event. Of this group, 75% developed secondary CRPS. CRPS in all four extremities occurred in six patients, of whom five had inciting events for each extremity.

copyright pixologicstudio/Thinkstock

lfranki@frontlinemedcom.com

Secondary complex regional pain syndrome is significantly more likely in people currently experiencing CRPS in an unrelated extremity than in the general population, according to Ellen Satteson, MD, and her associates.

In a study of 93 patients with CRPS, 20.4% developed secondary CRPS in another extremity. Twenty patients in the primary CRPS group experienced a secondary inciting event. Of this group, 75% developed secondary CRPS. CRPS in all four extremities occurred in six patients, of whom five had inciting events for each extremity.

copyright pixologicstudio/Thinkstock

lfranki@frontlinemedcom.com

Secondary complex regional pain syndrome is significantly more likely in people currently experiencing CRPS in an unrelated extremity than in the general population, according to Ellen Satteson, MD, and her associates.

In a study of 93 patients with CRPS, 20.4% developed secondary CRPS in another extremity. Twenty patients in the primary CRPS group experienced a secondary inciting event. Of this group, 75% developed secondary CRPS. CRPS in all four extremities occurred in six patients, of whom five had inciting events for each extremity.

copyright pixologicstudio/Thinkstock

lfranki@frontlinemedcom.com

Increases in inflammatory markers during acute psychosis suggest that higher C-reactive protein levels in adolescence may play an important role in subsequent schizophrenia by age 27, but more study is needed, results from a longitudinal study suggest.

“Inflammatory pathways may offer important new prevention and intervention targets for schizophrenia,” wrote Stephen A. Metcalf of the University of Cambridge (England) and his coauthors, most of whom are based in Finland (Brain Behav Immun. 2017 Jan;59:253-9).

The birth cohort consisted of 99% of the live births in two northern Finland provinces between July 1985 and June 1986. Investigators studied 6,362 individuals within the cohort who had gone on to have their blood sampled at age 15 or 16 years and measured for levels of serum C-reactive protein (CRP).

Increased levels of CRP are associated with antipsychotic-naive first-episode psychosis and acute psychotic relapse. However, “it is difficult to ascertain the direction of association between inflammation and schizophrenia from cross-sectional data. Longitudinal studies of inflammatory markers and subsequent psychotic illness are scarce but are necessary to establish whether the increase in circulating inflammatory markers is a cause or consequence of illness,” wrote Mr. Metcalf and his coauthors.

The investigators searched Finnish hospital records for cases and ICD-10 diagnoses of nonaffective psychosis, including schizophrenia, for the years 1994 to 2012 for CRP-measured members of the birth cohort, spanning ages 8-27 years. With the records collected, they sorted the participants for analysis into the following three groups: schizophrenia (n = 22), nonschizophrenia nonaffective psychosis (n = 66), and no psychosis (n = 6,274).

“The adjusted [odds ratio] for schizophrenia by age 27 years for each standard deviation increase in CRP levels at age 15/16 years was 1.25 (95% confidence interval, 1.07-1.46), which was consistent with a linear, dose-response relationship (P = 0.23),” Mr. Metcalf and his coauthors wrote. Participants with high levels of CRP at baseline (greater than 3 mg/L), compared with low levels (less than 1 mg/L), were more likely to develop schizophrenia (adjusted OR, 4.25; 95% CI, 1.30-13.93).

The investigators adjusted their regression models for age, sex, body mass index, maternal education, smoking, and alcohol use. “To exclude reverse causality (i.e., schizophrenia leading to elevated CRP), we repeated the analyses after removing participants who had developed schizophrenia within one year of CRP assay.”

The findings build on those from a longitudinal study in Denmark on increased risks for schizophrenia associated with higher CRP levels (Schizophr Bull. 2014 Sep;40[5]:1117-27). The authors cautioned that the current findings must be replicated elsewhere.

The authors disclosed several individual funding sources, but none played a role in the study.

dwatson@frontlinemedcom.com

Increases in inflammatory markers during acute psychosis suggest that higher C-reactive protein levels in adolescence may play an important role in subsequent schizophrenia by age 27, but more study is needed, results from a longitudinal study suggest.

“Inflammatory pathways may offer important new prevention and intervention targets for schizophrenia,” wrote Stephen A. Metcalf of the University of Cambridge (England) and his coauthors, most of whom are based in Finland (Brain Behav Immun. 2017 Jan;59:253-9).

The birth cohort consisted of 99% of the live births in two northern Finland provinces between July 1985 and June 1986. Investigators studied 6,362 individuals within the cohort who had gone on to have their blood sampled at age 15 or 16 years and measured for levels of serum C-reactive protein (CRP).

Increased levels of CRP are associated with antipsychotic-naive first-episode psychosis and acute psychotic relapse. However, “it is difficult to ascertain the direction of association between inflammation and schizophrenia from cross-sectional data. Longitudinal studies of inflammatory markers and subsequent psychotic illness are scarce but are necessary to establish whether the increase in circulating inflammatory markers is a cause or consequence of illness,” wrote Mr. Metcalf and his coauthors.

The investigators searched Finnish hospital records for cases and ICD-10 diagnoses of nonaffective psychosis, including schizophrenia, for the years 1994 to 2012 for CRP-measured members of the birth cohort, spanning ages 8-27 years. With the records collected, they sorted the participants for analysis into the following three groups: schizophrenia (n = 22), nonschizophrenia nonaffective psychosis (n = 66), and no psychosis (n = 6,274).

“The adjusted [odds ratio] for schizophrenia by age 27 years for each standard deviation increase in CRP levels at age 15/16 years was 1.25 (95% confidence interval, 1.07-1.46), which was consistent with a linear, dose-response relationship (P = 0.23),” Mr. Metcalf and his coauthors wrote. Participants with high levels of CRP at baseline (greater than 3 mg/L), compared with low levels (less than 1 mg/L), were more likely to develop schizophrenia (adjusted OR, 4.25; 95% CI, 1.30-13.93).

The investigators adjusted their regression models for age, sex, body mass index, maternal education, smoking, and alcohol use. “To exclude reverse causality (i.e., schizophrenia leading to elevated CRP), we repeated the analyses after removing participants who had developed schizophrenia within one year of CRP assay.”

The findings build on those from a longitudinal study in Denmark on increased risks for schizophrenia associated with higher CRP levels (Schizophr Bull. 2014 Sep;40[5]:1117-27). The authors cautioned that the current findings must be replicated elsewhere.

The authors disclosed several individual funding sources, but none played a role in the study.

dwatson@frontlinemedcom.com

Increases in inflammatory markers during acute psychosis suggest that higher C-reactive protein levels in adolescence may play an important role in subsequent schizophrenia by age 27, but more study is needed, results from a longitudinal study suggest.

“Inflammatory pathways may offer important new prevention and intervention targets for schizophrenia,” wrote Stephen A. Metcalf of the University of Cambridge (England) and his coauthors, most of whom are based in Finland (Brain Behav Immun. 2017 Jan;59:253-9).

The birth cohort consisted of 99% of the live births in two northern Finland provinces between July 1985 and June 1986. Investigators studied 6,362 individuals within the cohort who had gone on to have their blood sampled at age 15 or 16 years and measured for levels of serum C-reactive protein (CRP).

Increased levels of CRP are associated with antipsychotic-naive first-episode psychosis and acute psychotic relapse. However, “it is difficult to ascertain the direction of association between inflammation and schizophrenia from cross-sectional data. Longitudinal studies of inflammatory markers and subsequent psychotic illness are scarce but are necessary to establish whether the increase in circulating inflammatory markers is a cause or consequence of illness,” wrote Mr. Metcalf and his coauthors.

The investigators searched Finnish hospital records for cases and ICD-10 diagnoses of nonaffective psychosis, including schizophrenia, for the years 1994 to 2012 for CRP-measured members of the birth cohort, spanning ages 8-27 years. With the records collected, they sorted the participants for analysis into the following three groups: schizophrenia (n = 22), nonschizophrenia nonaffective psychosis (n = 66), and no psychosis (n = 6,274).

“The adjusted [odds ratio] for schizophrenia by age 27 years for each standard deviation increase in CRP levels at age 15/16 years was 1.25 (95% confidence interval, 1.07-1.46), which was consistent with a linear, dose-response relationship (P = 0.23),” Mr. Metcalf and his coauthors wrote. Participants with high levels of CRP at baseline (greater than 3 mg/L), compared with low levels (less than 1 mg/L), were more likely to develop schizophrenia (adjusted OR, 4.25; 95% CI, 1.30-13.93).

The investigators adjusted their regression models for age, sex, body mass index, maternal education, smoking, and alcohol use. “To exclude reverse causality (i.e., schizophrenia leading to elevated CRP), we repeated the analyses after removing participants who had developed schizophrenia within one year of CRP assay.”

The findings build on those from a longitudinal study in Denmark on increased risks for schizophrenia associated with higher CRP levels (Schizophr Bull. 2014 Sep;40[5]:1117-27). The authors cautioned that the current findings must be replicated elsewhere.

The authors disclosed several individual funding sources, but none played a role in the study.

dwatson@frontlinemedcom.com

SAN DIEGO – The antiamyloid antibody aducanumab significantly reduced amyloid brain plaques in Alzheimer’s disease patients who entered a second year of therapy in an open-label extension trial.

Plaque volume declined in a time- and dose-dependent manner, with a bit of movement even among patients who crossed over to the lowest 1-mg/kg dose after a year of taking placebo in the phase Ib PRIME study, Samantha Haeberlein, PhD, reported at the Clinical Trials on Alzheimer’s Disease conference.

The linear declines in plaque burden were dramatic enough to draw a collective gasp of appreciation from the packed auditorium. But the cognitive and functional data of aducanumab (Biogen), while deemed encouraging, were not as striking. The Clinical Dementia Rating Scale-sum of boxes (CDR-SB) and the Mini-Mental State Examination (MMSE) showed dose-dependent slowing of decline, but the drug’s effect approached statistical significance only among those who finished 2 years on 10 mg/kg aducanumab infused every 4 weeks. This group experienced relative stability of MMSE scores, which dropped only about 1 point from baseline, and also showed the greatest decline in amyloid plaque volume.

Biogen deemed this result on the MMSE, which represented a 3.27-point separation from the 1-mg/kg dose group, as “nominally significant,” with a P value noted as “less than .05.”

However, the finding must be viewed with extreme caution, said Dr. Haeberlein, Biogen’s vice president of clinical development. There were only 15 subjects in this group, and the study was not primarily intended to examine cognition.

“I must emphasize once again that these are exploratory data and these sample sizes are very small for these types of assessments,” she said. “Nonetheless, we find them informative.”

MMSE changes in the other dosing groups of 1, 3, and 6 mg/kg were not statistically significant at the end of the study. There were not any significant findings on the CDR-SB measure.

Alzheimer’s Association reaction

Maria C. Carrillo, PhD, chief science officer of the Alzheimer’s Association, was cautiously optimistic.

Full 12-month results

Biogen presented two aducanumab abstracts at the meeting, both describing its 12-month phase Ib PRIME study and its 12-month, open-label extension study. The drug is a monoclonal human antibody derived from B cells collected from a cohort of cognitively normal elderly subjects and cognitively impaired elderly subjects who exhibited unusually slow decline, according to the company. It binds to fibrillar and oligomeric amyloid aggregates, thus directly reducing amyloid plaque in the brain.

PRIME enrolled 165 patients with prodromal or mild Alzheimer’s disease. Importantly, all of the subjects had brain amyloid proven by PET imaging. PRIME is the first randomized trial of an antiamyloid compound to enroll a pure amyloid-positive cohort. These subjects were randomized to placebo or aducanumab at 1, 3, 6, or 10 mg/kg for 1 year. PRIME’s primary outcomes were safety and tolerability. The cognitive and functional outcomes, not usually assessed in a phase Ib study, were exploratory.

They must also be interpreted in light of the very small numbers, about 30 patients in each dosing group at baseline. In addition, just 69 patients finished the entire 24-month dosing period, leaving only 15-23 patients in each group by the end of the study.

Vissia Viglietta, MD, Biogen’s senior medical director of clinical development, presented the 12-month data. At 52 weeks, all dosing groups, even the 1 mg/kg, saw statistically significant reductions in amyloid plaque, compared with placebo. These changes were dose-dependent; the 10-mg/kg group had the largest reduction, with a P value of less than .001.

There also were dose-dependent changes in the CDR-SB and MMSE, and some of these reached statistical significance.

On the CDR-SB, patients taking placebo declined by an average of 1.89 points. Declines in the 1-, 3-, and 6-mg/kg groups were not significant relative to placebo. However, the 10-mg/kg arm experienced a significant separation from placebo, declining an average of 0.63 points (P less than .05).

The story was similar for the MMSE. Patients taking placebo declined by 2.45 points. The decline was 2.2 points in the 1-mg/kg group; 0.75 in the 3-mg/kg group; and 0.55 in the 10-mg/kg group. The only statistically significant results relative to placebo occurred with the 10-mg/kg group (P less than .05).

The 6-mg/kg group didn’t fit this pattern though, losing an average of 2 points. Biogen has been unable to explain this, but some researchers suggest such an outlying result isn’t surprising, given the small numbers in each group and the exploratory nature of the cognitive analysis.

Amyloid-related imaging abnormalities (ARIA), an inflammatory reaction thought to be related to the removal of amyloid plaque, were the most common adverse event (n = 27). Most of these (22) were in apolipoprotein E4 allele carriers.

Two patients in the placebo arm died, as well as one in the 10-mg/kg arm, but it was not considered related to the study drug. There were no significant changes in hematology, chemistry, urinalysis, electrocardiogram, or vital signs.

Open-label extension results

Dr. Haeberlein focused on the subsequent 12-month, open-label extension trial, which enrolled 117 of the randomized cohort. In this study, patients who had been taking placebo were switched to either 3- or 6-mg/kg aducanumab. Patients who had taken 1 mg/kg were switched to 3 mg/kg. By the end, the remaining patients had taken the antibody for 2 years.

By 24 months, all the dosing groups showed a continued, linear reduction of amyloid plaques. Even those who switched from placebo to 3 mg/kg started to experience plaque reduction, although of a lesser magnitude than with the higher doses.

While still expressing caution, Dr. Haeberlein framed the CDR-SB results as very positive. The placebo and 1-mg/kg switchers continued to progress, but for those who continued on the 3-, 6-, and 10-mg/kg doses, “we saw a saw a numerical slowing of disease progression at both 18 and 24 months.”

However, none of the changes in CDR-SB scores reached statistical significance.

The numbers were somewhat more encouraging in the MMSE analysis. The 3- and 10-mg/kg groups began to separate at 12 months. By 24 months, the 10-mg/kg group had lost about 1 point on the MMSE while there were declines of about 2 points in the 3-mg/kg group and about 3 points in the 1-mg/kg group. Again, the 6-mg/kg group was an outlier, losing about 5 points.

“We already observed that this group behaved differently at 12 months on this endpoint, and we saw that particular cohort continued to follow that trend,” Dr. Haeberlein said.

There were 16 cases of ARIA in the extension trial. Eight were ARIA accompanied by vascular edema (ARIA-E) and these all occurred in the placebo and 1-mg/kg switchers. Three patients discontinued due to ARIA-E.

The remaining eight cases of ARIA were accompanied by microhemorrhage (ARIA-H); these were distributed among all of the dosage groups.

One patient with ARIA-E experienced a seizure and transient loss of pulse. Dr. Haeberlein didn’t elaborate on the possible cause of this event. Two additional patients died, with neither death judged related to the study medication.

The safety data, combined with the reduction of amyloid plaque and hints of cognitive and functional benefit, are enough to continue developing aducanumab, Dr. Haeberlein said. Biogen is recruiting 2,700 subjects with mild cognitive impairment or mild Alzheimer’s for identical phase III studies dubbed ENGAGE and EMERGE.

msullivan@frontlinemedcom.com

On Twitter @alz_gal

SAN DIEGO – The antiamyloid antibody aducanumab significantly reduced amyloid brain plaques in Alzheimer’s disease patients who entered a second year of therapy in an open-label extension trial.

Plaque volume declined in a time- and dose-dependent manner, with a bit of movement even among patients who crossed over to the lowest 1-mg/kg dose after a year of taking placebo in the phase Ib PRIME study, Samantha Haeberlein, PhD, reported at the Clinical Trials on Alzheimer’s Disease conference.

The linear declines in plaque burden were dramatic enough to draw a collective gasp of appreciation from the packed auditorium. But the cognitive and functional data of aducanumab (Biogen), while deemed encouraging, were not as striking. The Clinical Dementia Rating Scale-sum of boxes (CDR-SB) and the Mini-Mental State Examination (MMSE) showed dose-dependent slowing of decline, but the drug’s effect approached statistical significance only among those who finished 2 years on 10 mg/kg aducanumab infused every 4 weeks. This group experienced relative stability of MMSE scores, which dropped only about 1 point from baseline, and also showed the greatest decline in amyloid plaque volume.

Biogen deemed this result on the MMSE, which represented a 3.27-point separation from the 1-mg/kg dose group, as “nominally significant,” with a P value noted as “less than .05.”

However, the finding must be viewed with extreme caution, said Dr. Haeberlein, Biogen’s vice president of clinical development. There were only 15 subjects in this group, and the study was not primarily intended to examine cognition.

“I must emphasize once again that these are exploratory data and these sample sizes are very small for these types of assessments,” she said. “Nonetheless, we find them informative.”

MMSE changes in the other dosing groups of 1, 3, and 6 mg/kg were not statistically significant at the end of the study. There were not any significant findings on the CDR-SB measure.

Alzheimer’s Association reaction

Maria C. Carrillo, PhD, chief science officer of the Alzheimer’s Association, was cautiously optimistic.

Full 12-month results

Biogen presented two aducanumab abstracts at the meeting, both describing its 12-month phase Ib PRIME study and its 12-month, open-label extension study. The drug is a monoclonal human antibody derived from B cells collected from a cohort of cognitively normal elderly subjects and cognitively impaired elderly subjects who exhibited unusually slow decline, according to the company. It binds to fibrillar and oligomeric amyloid aggregates, thus directly reducing amyloid plaque in the brain.

PRIME enrolled 165 patients with prodromal or mild Alzheimer’s disease. Importantly, all of the subjects had brain amyloid proven by PET imaging. PRIME is the first randomized trial of an antiamyloid compound to enroll a pure amyloid-positive cohort. These subjects were randomized to placebo or aducanumab at 1, 3, 6, or 10 mg/kg for 1 year. PRIME’s primary outcomes were safety and tolerability. The cognitive and functional outcomes, not usually assessed in a phase Ib study, were exploratory.

They must also be interpreted in light of the very small numbers, about 30 patients in each dosing group at baseline. In addition, just 69 patients finished the entire 24-month dosing period, leaving only 15-23 patients in each group by the end of the study.

Vissia Viglietta, MD, Biogen’s senior medical director of clinical development, presented the 12-month data. At 52 weeks, all dosing groups, even the 1 mg/kg, saw statistically significant reductions in amyloid plaque, compared with placebo. These changes were dose-dependent; the 10-mg/kg group had the largest reduction, with a P value of less than .001.

There also were dose-dependent changes in the CDR-SB and MMSE, and some of these reached statistical significance.

On the CDR-SB, patients taking placebo declined by an average of 1.89 points. Declines in the 1-, 3-, and 6-mg/kg groups were not significant relative to placebo. However, the 10-mg/kg arm experienced a significant separation from placebo, declining an average of 0.63 points (P less than .05).

The story was similar for the MMSE. Patients taking placebo declined by 2.45 points. The decline was 2.2 points in the 1-mg/kg group; 0.75 in the 3-mg/kg group; and 0.55 in the 10-mg/kg group. The only statistically significant results relative to placebo occurred with the 10-mg/kg group (P less than .05).

The 6-mg/kg group didn’t fit this pattern though, losing an average of 2 points. Biogen has been unable to explain this, but some researchers suggest such an outlying result isn’t surprising, given the small numbers in each group and the exploratory nature of the cognitive analysis.

Amyloid-related imaging abnormalities (ARIA), an inflammatory reaction thought to be related to the removal of amyloid plaque, were the most common adverse event (n = 27). Most of these (22) were in apolipoprotein E4 allele carriers.

Two patients in the placebo arm died, as well as one in the 10-mg/kg arm, but it was not considered related to the study drug. There were no significant changes in hematology, chemistry, urinalysis, electrocardiogram, or vital signs.

Open-label extension results

Dr. Haeberlein focused on the subsequent 12-month, open-label extension trial, which enrolled 117 of the randomized cohort. In this study, patients who had been taking placebo were switched to either 3- or 6-mg/kg aducanumab. Patients who had taken 1 mg/kg were switched to 3 mg/kg. By the end, the remaining patients had taken the antibody for 2 years.

By 24 months, all the dosing groups showed a continued, linear reduction of amyloid plaques. Even those who switched from placebo to 3 mg/kg started to experience plaque reduction, although of a lesser magnitude than with the higher doses.

While still expressing caution, Dr. Haeberlein framed the CDR-SB results as very positive. The placebo and 1-mg/kg switchers continued to progress, but for those who continued on the 3-, 6-, and 10-mg/kg doses, “we saw a saw a numerical slowing of disease progression at both 18 and 24 months.”

However, none of the changes in CDR-SB scores reached statistical significance.

The numbers were somewhat more encouraging in the MMSE analysis. The 3- and 10-mg/kg groups began to separate at 12 months. By 24 months, the 10-mg/kg group had lost about 1 point on the MMSE while there were declines of about 2 points in the 3-mg/kg group and about 3 points in the 1-mg/kg group. Again, the 6-mg/kg group was an outlier, losing about 5 points.

“We already observed that this group behaved differently at 12 months on this endpoint, and we saw that particular cohort continued to follow that trend,” Dr. Haeberlein said.

There were 16 cases of ARIA in the extension trial. Eight were ARIA accompanied by vascular edema (ARIA-E) and these all occurred in the placebo and 1-mg/kg switchers. Three patients discontinued due to ARIA-E.

The remaining eight cases of ARIA were accompanied by microhemorrhage (ARIA-H); these were distributed among all of the dosage groups.

One patient with ARIA-E experienced a seizure and transient loss of pulse. Dr. Haeberlein didn’t elaborate on the possible cause of this event. Two additional patients died, with neither death judged related to the study medication.

The safety data, combined with the reduction of amyloid plaque and hints of cognitive and functional benefit, are enough to continue developing aducanumab, Dr. Haeberlein said. Biogen is recruiting 2,700 subjects with mild cognitive impairment or mild Alzheimer’s for identical phase III studies dubbed ENGAGE and EMERGE.

msullivan@frontlinemedcom.com

On Twitter @alz_gal

SAN DIEGO – The antiamyloid antibody aducanumab significantly reduced amyloid brain plaques in Alzheimer’s disease patients who entered a second year of therapy in an open-label extension trial.

Plaque volume declined in a time- and dose-dependent manner, with a bit of movement even among patients who crossed over to the lowest 1-mg/kg dose after a year of taking placebo in the phase Ib PRIME study, Samantha Haeberlein, PhD, reported at the Clinical Trials on Alzheimer’s Disease conference.

The linear declines in plaque burden were dramatic enough to draw a collective gasp of appreciation from the packed auditorium. But the cognitive and functional data of aducanumab (Biogen), while deemed encouraging, were not as striking. The Clinical Dementia Rating Scale-sum of boxes (CDR-SB) and the Mini-Mental State Examination (MMSE) showed dose-dependent slowing of decline, but the drug’s effect approached statistical significance only among those who finished 2 years on 10 mg/kg aducanumab infused every 4 weeks. This group experienced relative stability of MMSE scores, which dropped only about 1 point from baseline, and also showed the greatest decline in amyloid plaque volume.

Biogen deemed this result on the MMSE, which represented a 3.27-point separation from the 1-mg/kg dose group, as “nominally significant,” with a P value noted as “less than .05.”

However, the finding must be viewed with extreme caution, said Dr. Haeberlein, Biogen’s vice president of clinical development. There were only 15 subjects in this group, and the study was not primarily intended to examine cognition.

“I must emphasize once again that these are exploratory data and these sample sizes are very small for these types of assessments,” she said. “Nonetheless, we find them informative.”

MMSE changes in the other dosing groups of 1, 3, and 6 mg/kg were not statistically significant at the end of the study. There were not any significant findings on the CDR-SB measure.

Alzheimer’s Association reaction

Maria C. Carrillo, PhD, chief science officer of the Alzheimer’s Association, was cautiously optimistic.

Full 12-month results

Biogen presented two aducanumab abstracts at the meeting, both describing its 12-month phase Ib PRIME study and its 12-month, open-label extension study. The drug is a monoclonal human antibody derived from B cells collected from a cohort of cognitively normal elderly subjects and cognitively impaired elderly subjects who exhibited unusually slow decline, according to the company. It binds to fibrillar and oligomeric amyloid aggregates, thus directly reducing amyloid plaque in the brain.

PRIME enrolled 165 patients with prodromal or mild Alzheimer’s disease. Importantly, all of the subjects had brain amyloid proven by PET imaging. PRIME is the first randomized trial of an antiamyloid compound to enroll a pure amyloid-positive cohort. These subjects were randomized to placebo or aducanumab at 1, 3, 6, or 10 mg/kg for 1 year. PRIME’s primary outcomes were safety and tolerability. The cognitive and functional outcomes, not usually assessed in a phase Ib study, were exploratory.

They must also be interpreted in light of the very small numbers, about 30 patients in each dosing group at baseline. In addition, just 69 patients finished the entire 24-month dosing period, leaving only 15-23 patients in each group by the end of the study.

Vissia Viglietta, MD, Biogen’s senior medical director of clinical development, presented the 12-month data. At 52 weeks, all dosing groups, even the 1 mg/kg, saw statistically significant reductions in amyloid plaque, compared with placebo. These changes were dose-dependent; the 10-mg/kg group had the largest reduction, with a P value of less than .001.

There also were dose-dependent changes in the CDR-SB and MMSE, and some of these reached statistical significance.

On the CDR-SB, patients taking placebo declined by an average of 1.89 points. Declines in the 1-, 3-, and 6-mg/kg groups were not significant relative to placebo. However, the 10-mg/kg arm experienced a significant separation from placebo, declining an average of 0.63 points (P less than .05).

The story was similar for the MMSE. Patients taking placebo declined by 2.45 points. The decline was 2.2 points in the 1-mg/kg group; 0.75 in the 3-mg/kg group; and 0.55 in the 10-mg/kg group. The only statistically significant results relative to placebo occurred with the 10-mg/kg group (P less than .05).

The 6-mg/kg group didn’t fit this pattern though, losing an average of 2 points. Biogen has been unable to explain this, but some researchers suggest such an outlying result isn’t surprising, given the small numbers in each group and the exploratory nature of the cognitive analysis.

Amyloid-related imaging abnormalities (ARIA), an inflammatory reaction thought to be related to the removal of amyloid plaque, were the most common adverse event (n = 27). Most of these (22) were in apolipoprotein E4 allele carriers.

Two patients in the placebo arm died, as well as one in the 10-mg/kg arm, but it was not considered related to the study drug. There were no significant changes in hematology, chemistry, urinalysis, electrocardiogram, or vital signs.

Open-label extension results

Dr. Haeberlein focused on the subsequent 12-month, open-label extension trial, which enrolled 117 of the randomized cohort. In this study, patients who had been taking placebo were switched to either 3- or 6-mg/kg aducanumab. Patients who had taken 1 mg/kg were switched to 3 mg/kg. By the end, the remaining patients had taken the antibody for 2 years.

By 24 months, all the dosing groups showed a continued, linear reduction of amyloid plaques. Even those who switched from placebo to 3 mg/kg started to experience plaque reduction, although of a lesser magnitude than with the higher doses.

While still expressing caution, Dr. Haeberlein framed the CDR-SB results as very positive. The placebo and 1-mg/kg switchers continued to progress, but for those who continued on the 3-, 6-, and 10-mg/kg doses, “we saw a saw a numerical slowing of disease progression at both 18 and 24 months.”

However, none of the changes in CDR-SB scores reached statistical significance.

The numbers were somewhat more encouraging in the MMSE analysis. The 3- and 10-mg/kg groups began to separate at 12 months. By 24 months, the 10-mg/kg group had lost about 1 point on the MMSE while there were declines of about 2 points in the 3-mg/kg group and about 3 points in the 1-mg/kg group. Again, the 6-mg/kg group was an outlier, losing about 5 points.

“We already observed that this group behaved differently at 12 months on this endpoint, and we saw that particular cohort continued to follow that trend,” Dr. Haeberlein said.

There were 16 cases of ARIA in the extension trial. Eight were ARIA accompanied by vascular edema (ARIA-E) and these all occurred in the placebo and 1-mg/kg switchers. Three patients discontinued due to ARIA-E.

The remaining eight cases of ARIA were accompanied by microhemorrhage (ARIA-H); these were distributed among all of the dosage groups.

One patient with ARIA-E experienced a seizure and transient loss of pulse. Dr. Haeberlein didn’t elaborate on the possible cause of this event. Two additional patients died, with neither death judged related to the study medication.

The safety data, combined with the reduction of amyloid plaque and hints of cognitive and functional benefit, are enough to continue developing aducanumab, Dr. Haeberlein said. Biogen is recruiting 2,700 subjects with mild cognitive impairment or mild Alzheimer’s for identical phase III studies dubbed ENGAGE and EMERGE.

msullivan@frontlinemedcom.com

On Twitter @alz_gal