BALTIMORE – Candidates for epilepsy surgery who are employed are significantly more likely to decline surgery than are those who are unemployed, according to an analysis presented at the annual meeting of the American Epilepsy Society. “Future work should confirm this finding prospectively, determine if it holds in other patient populations, and explore the decision to proceed with or decline epilepsy surgery from a patient-centered perspective,” said Vishal Mandge, MD, MPH, a clinical neurophysiology fellow at Duke University in Durham, N.C., and colleagues. “Identifying the role that factors such as the fear of losing employment due to complications from surgery and inability to take medical leave for an extended period of time play in the patient’s decision to proceed with epilepsy surgery may identify needs and suggest strategies to reduce barriers to this underutilized treatment.”

Although epilepsy surgery is known to be safe and effective, many surgical candidates with drug-resistant epilepsy decline to undergo the procedure. Prior investigations of the barriers to epilepsy surgery have focused on access to epilepsy centers that offer epilepsy surgery and patients’ reluctance to undergo presurgical evaluation. Dr. Mandge and colleagues instead set out to evaluate the association between various demographic, disease-specific, and epilepsy-evaluation variables and patients’ decision to decline surgery after they have been identified as candidates.
 

A retrospective case-control study

The investigators conducted a retrospective case-control study of patients who were discussed at the epilepsy surgery conference of a tertiary care hospital serving an urban New York community between Jan. 1, 2009, and June 30, 2017. They identified patients who were considered candidates for resective epilepsy surgery. Dr. Mandge and colleagues used the chi-squared test for nominal variables and analysis of variance for scale variables to evaluate these variables’ associations with a patient’s decision to decline epilepsy surgery. They also performed multivariate binary logistic regression to identify variables that predict a patient’s decision to decline surgery.

Dr. Mandge and colleagues identified 159 patients who were discussed during the study period. Of this group, 87 patients were eligible for resective epilepsy surgery after a thorough evaluation. Thirty-four (40%) of the eligible patients declined to undergo surgery. Approximately 20% of eligible patients were employed, and 70% of patients had a high school diploma or higher education.

Univariate analysis indicated that employment (odds ratio, 4.2), temporal lesion on MRI (OR, 0.35), temporal EEG localization (OR, 0.21), and temporal seizure onset zone (OR, 0.19) were independently and significantly associated with a patient’s decision to decline surgery. Multivariate logistic regression analysis indicated that current employment (OR, 7.5), the number of current antiepileptic drugs (AEDs; OR, 3.5), and concordance between seizure semiology, seizure onset on EEG, and imaging (OR, 0.08) were significantly associated with a patient’s decision to decline surgery.
 

Fear of unemployment may explain results

“With each additional AED, the patients were 3.5 times more likely to decline surgery, even after adjusting for other variables,” said Alexis D. Boro, MD, a neurologist at Montefiore Medical Center in New York and one of the investigators. “My suspicion is that some of this reflects the burden of taking a lot of seizure medication. While the medications are much, much safer than seizures, and looking for and dealing with side effects is a lot of what we do, people often don’t feel great when they are taking multiple seizure medications. We counsel our patients that they should generally expect to stay on some seizure medications after surgery. The reason for surgery is to stop the seizures, not to stop the medications. We are often able to reduce medications after a period of time after surgery, and for many patients, this is one of the benefits.”

The association between employment and increased likelihood of declining surgery was unexpected and may not hold everywhere, said Dr. Boro. “We had expected the opposite result because we assumed that employed patients would be concerned that a seizure at work might result in loss of work. But it may be that many of our patients who are employed are concerned about losing their jobs if they miss work for a medical procedure. Some of our patients may be concerned about sharing medical information with their employers. For some of our patients, being employed may imply limited insurance coverage.”

The study was not supported by external funding, and the investigators did not report any disclosures.

[email protected]

SOURCE: Mandge VA et al. AES 2019, Abstract 1.362.

BALTIMORE – Candidates for epilepsy surgery who are employed are significantly more likely to decline surgery than are those who are unemployed, according to an analysis presented at the annual meeting of the American Epilepsy Society. “Future work should confirm this finding prospectively, determine if it holds in other patient populations, and explore the decision to proceed with or decline epilepsy surgery from a patient-centered perspective,” said Vishal Mandge, MD, MPH, a clinical neurophysiology fellow at Duke University in Durham, N.C., and colleagues. “Identifying the role that factors such as the fear of losing employment due to complications from surgery and inability to take medical leave for an extended period of time play in the patient’s decision to proceed with epilepsy surgery may identify needs and suggest strategies to reduce barriers to this underutilized treatment.”

Although epilepsy surgery is known to be safe and effective, many surgical candidates with drug-resistant epilepsy decline to undergo the procedure. Prior investigations of the barriers to epilepsy surgery have focused on access to epilepsy centers that offer epilepsy surgery and patients’ reluctance to undergo presurgical evaluation. Dr. Mandge and colleagues instead set out to evaluate the association between various demographic, disease-specific, and epilepsy-evaluation variables and patients’ decision to decline surgery after they have been identified as candidates.
 

A retrospective case-control study

The investigators conducted a retrospective case-control study of patients who were discussed at the epilepsy surgery conference of a tertiary care hospital serving an urban New York community between Jan. 1, 2009, and June 30, 2017. They identified patients who were considered candidates for resective epilepsy surgery. Dr. Mandge and colleagues used the chi-squared test for nominal variables and analysis of variance for scale variables to evaluate these variables’ associations with a patient’s decision to decline epilepsy surgery. They also performed multivariate binary logistic regression to identify variables that predict a patient’s decision to decline surgery.

Dr. Mandge and colleagues identified 159 patients who were discussed during the study period. Of this group, 87 patients were eligible for resective epilepsy surgery after a thorough evaluation. Thirty-four (40%) of the eligible patients declined to undergo surgery. Approximately 20% of eligible patients were employed, and 70% of patients had a high school diploma or higher education.

Univariate analysis indicated that employment (odds ratio, 4.2), temporal lesion on MRI (OR, 0.35), temporal EEG localization (OR, 0.21), and temporal seizure onset zone (OR, 0.19) were independently and significantly associated with a patient’s decision to decline surgery. Multivariate logistic regression analysis indicated that current employment (OR, 7.5), the number of current antiepileptic drugs (AEDs; OR, 3.5), and concordance between seizure semiology, seizure onset on EEG, and imaging (OR, 0.08) were significantly associated with a patient’s decision to decline surgery.
 

Fear of unemployment may explain results

“With each additional AED, the patients were 3.5 times more likely to decline surgery, even after adjusting for other variables,” said Alexis D. Boro, MD, a neurologist at Montefiore Medical Center in New York and one of the investigators. “My suspicion is that some of this reflects the burden of taking a lot of seizure medication. While the medications are much, much safer than seizures, and looking for and dealing with side effects is a lot of what we do, people often don’t feel great when they are taking multiple seizure medications. We counsel our patients that they should generally expect to stay on some seizure medications after surgery. The reason for surgery is to stop the seizures, not to stop the medications. We are often able to reduce medications after a period of time after surgery, and for many patients, this is one of the benefits.”

The association between employment and increased likelihood of declining surgery was unexpected and may not hold everywhere, said Dr. Boro. “We had expected the opposite result because we assumed that employed patients would be concerned that a seizure at work might result in loss of work. But it may be that many of our patients who are employed are concerned about losing their jobs if they miss work for a medical procedure. Some of our patients may be concerned about sharing medical information with their employers. For some of our patients, being employed may imply limited insurance coverage.”

The study was not supported by external funding, and the investigators did not report any disclosures.

[email protected]

SOURCE: Mandge VA et al. AES 2019, Abstract 1.362.

BALTIMORE – Candidates for epilepsy surgery who are employed are significantly more likely to decline surgery than are those who are unemployed, according to an analysis presented at the annual meeting of the American Epilepsy Society. “Future work should confirm this finding prospectively, determine if it holds in other patient populations, and explore the decision to proceed with or decline epilepsy surgery from a patient-centered perspective,” said Vishal Mandge, MD, MPH, a clinical neurophysiology fellow at Duke University in Durham, N.C., and colleagues. “Identifying the role that factors such as the fear of losing employment due to complications from surgery and inability to take medical leave for an extended period of time play in the patient’s decision to proceed with epilepsy surgery may identify needs and suggest strategies to reduce barriers to this underutilized treatment.”

Although epilepsy surgery is known to be safe and effective, many surgical candidates with drug-resistant epilepsy decline to undergo the procedure. Prior investigations of the barriers to epilepsy surgery have focused on access to epilepsy centers that offer epilepsy surgery and patients’ reluctance to undergo presurgical evaluation. Dr. Mandge and colleagues instead set out to evaluate the association between various demographic, disease-specific, and epilepsy-evaluation variables and patients’ decision to decline surgery after they have been identified as candidates.
 

A retrospective case-control study

The investigators conducted a retrospective case-control study of patients who were discussed at the epilepsy surgery conference of a tertiary care hospital serving an urban New York community between Jan. 1, 2009, and June 30, 2017. They identified patients who were considered candidates for resective epilepsy surgery. Dr. Mandge and colleagues used the chi-squared test for nominal variables and analysis of variance for scale variables to evaluate these variables’ associations with a patient’s decision to decline epilepsy surgery. They also performed multivariate binary logistic regression to identify variables that predict a patient’s decision to decline surgery.

Dr. Mandge and colleagues identified 159 patients who were discussed during the study period. Of this group, 87 patients were eligible for resective epilepsy surgery after a thorough evaluation. Thirty-four (40%) of the eligible patients declined to undergo surgery. Approximately 20% of eligible patients were employed, and 70% of patients had a high school diploma or higher education.

Univariate analysis indicated that employment (odds ratio, 4.2), temporal lesion on MRI (OR, 0.35), temporal EEG localization (OR, 0.21), and temporal seizure onset zone (OR, 0.19) were independently and significantly associated with a patient’s decision to decline surgery. Multivariate logistic regression analysis indicated that current employment (OR, 7.5), the number of current antiepileptic drugs (AEDs; OR, 3.5), and concordance between seizure semiology, seizure onset on EEG, and imaging (OR, 0.08) were significantly associated with a patient’s decision to decline surgery.
 

Fear of unemployment may explain results

“With each additional AED, the patients were 3.5 times more likely to decline surgery, even after adjusting for other variables,” said Alexis D. Boro, MD, a neurologist at Montefiore Medical Center in New York and one of the investigators. “My suspicion is that some of this reflects the burden of taking a lot of seizure medication. While the medications are much, much safer than seizures, and looking for and dealing with side effects is a lot of what we do, people often don’t feel great when they are taking multiple seizure medications. We counsel our patients that they should generally expect to stay on some seizure medications after surgery. The reason for surgery is to stop the seizures, not to stop the medications. We are often able to reduce medications after a period of time after surgery, and for many patients, this is one of the benefits.”

The association between employment and increased likelihood of declining surgery was unexpected and may not hold everywhere, said Dr. Boro. “We had expected the opposite result because we assumed that employed patients would be concerned that a seizure at work might result in loss of work. But it may be that many of our patients who are employed are concerned about losing their jobs if they miss work for a medical procedure. Some of our patients may be concerned about sharing medical information with their employers. For some of our patients, being employed may imply limited insurance coverage.”

The study was not supported by external funding, and the investigators did not report any disclosures.

[email protected]

SOURCE: Mandge VA et al. AES 2019, Abstract 1.362.

In legal settings, the “sequential intercept model” for targeting people involved in the criminal justice system with mental illness has been proposed as an improvement for the status quo.

The model intends to divert individuals with mental illnesses at any one of five described stages in their journey through the legal system. In the first stage, a patient may be provided enough care in the community to never enter the criminal system. If that works, the patient may be diverted by first responders out of the legal system and back into treatment. Sequentially, throughout the remaining stages, the patient can be diverted by an attorney, the court, a presentencing correctional facility, the sentencing judge, a postsentencing correctional facility, or probation. The model rightfully encourages anyone in the continuum of care to take ownership of a situation and intervene.

I applaud the model for encouraging all participants to intervene in changing the course of our most challenging patients. However, I am reminded of the complexity of large systems trying to change. In practice, what I have seen is a series of half-hearted recommendations: Emergency responders who consider their role finished after giving a patient the number of the suicide hotline, attorneys who are satisfied by giving their clients an outdated list of community mental health clinics, judges who interpret their recommendations for treatment as a fait accompli, and correctional facilities that release patients with an absurdly short supply of medications and the address of an emergency room. I worry that by creating a model encouraging all to participate, we have just absolved ones who make any effort, even if inadequate.

In some ways, the sequential intercept model has similarities with modern mental health treatment teams. In many settings, a treatment team includes a series of providers who are sequentially involved in the life of a patient. A team can include a psychiatrist for psychopharmacology; a neuropsychologist for psychological testing; a social worker for psychotherapeutic strategies; another social worker to assist in obtaining social assistance; an addiction counselor for substance use disorder; another psychiatrist who monitors the administration of a single medication, like ketamine; and a pharmacist who approves the medication regimen. That’s several providers for the treatment of one patient.

As a forensic psychiatrist, I am often asked to review treatment plans of other providers. I am asked to comment on the appropriate nature of a given treatment. Often, insurance companies want to review the continued need for treatment or whether any treatment is warranted at all. Sometimes, employers want to review a treatment plan to ensure the safety of their employees. At times, courts will ask for a review and expectations from treatment of a defendant to assist in sentencing determinations. However, I have not yet been asked by anyone if the amount of care a patient is obtaining is too fragmented and without any clear leadership.

In our endless pursuit of medicalization and standardization of mental health, we have, especially in large systems, created specialization silos for the care of our patients. Many, if not most psychiatrists, do not participate in any psychotherapy; social workers and psychologists do not prescribe (for the most part); many substance abuse counselors only address sobriety and not other primary mental illness factors; and pharmacists cannot diagnose nor are they trained in psychosocial approaches. In many ways, we have defined participants not by what they do, but what they don’t do.

One also can be saddened by the enormous logistical complexity imposed on patients required to make numerous appointments, which can deprive them of time for recovery. However, my bigger concern is that the multiplicity of providers also permits the dissolution of accountability. In my experience, those large teams have an ability to deflect responsibility in ways that are unmatched by any single provider who cannot rely on putting the fault on someone else.

Sadly and ironically, those two parallel paradigms of mental illness and criminal care impose those problems on each other by averting any attempt at interception, a “no-intercept model.” Mental health programs will deny clients involved in the criminal justice system for requiring too much treatment, too little treatment, for lack of availability of one of the necessary providers, for requiring substance use treatment, or simply for being part of the criminal justice system. Accordingly, the legal system will fail to accept recommendations by mental health providers that mental health treatment is not paramount at this time and that the defendant would be better served by addressing his criminogenic risk factors. In response, the multitude of participants in the legal system will point to the mental health system for all answers.

Contrary to many if not most problems, I do not think that the solution lies somewhere in the middle, as this would require the five stages of the legal system to compromise with the nine hypothetical participants of the mental health system. I think that the solution lies in a resurgence of personal accountability and responsibility. For our part, as psychiatrists, we must accept that we are ultimately responsible for all levels of care. As a field, we are also responsible for educating the public and the legal system of our role and limitations in providing care as well as being available for providing such care. Correspondingly, the legal system is responsible for putting an adequate effort into diverting patients and having or obtaining adequate understanding of available and appropriate care for their defendants.
 

Dr. Badre is a forensic psychiatrist in San Diego and an expert in correctional mental health. He holds teaching positions at the University of California, San Diego, and the University of San Diego. He teaches medical education, psychopharmacology, ethics in psychiatry, and correctional care. Among his writings is chapter 7 in the new book “Critical Psychiatry: Controversies and Clinical Implications” (Springer, 2019).

In legal settings, the “sequential intercept model” for targeting people involved in the criminal justice system with mental illness has been proposed as an improvement for the status quo.

The model intends to divert individuals with mental illnesses at any one of five described stages in their journey through the legal system. In the first stage, a patient may be provided enough care in the community to never enter the criminal system. If that works, the patient may be diverted by first responders out of the legal system and back into treatment. Sequentially, throughout the remaining stages, the patient can be diverted by an attorney, the court, a presentencing correctional facility, the sentencing judge, a postsentencing correctional facility, or probation. The model rightfully encourages anyone in the continuum of care to take ownership of a situation and intervene.

I applaud the model for encouraging all participants to intervene in changing the course of our most challenging patients. However, I am reminded of the complexity of large systems trying to change. In practice, what I have seen is a series of half-hearted recommendations: Emergency responders who consider their role finished after giving a patient the number of the suicide hotline, attorneys who are satisfied by giving their clients an outdated list of community mental health clinics, judges who interpret their recommendations for treatment as a fait accompli, and correctional facilities that release patients with an absurdly short supply of medications and the address of an emergency room. I worry that by creating a model encouraging all to participate, we have just absolved ones who make any effort, even if inadequate.

In some ways, the sequential intercept model has similarities with modern mental health treatment teams. In many settings, a treatment team includes a series of providers who are sequentially involved in the life of a patient. A team can include a psychiatrist for psychopharmacology; a neuropsychologist for psychological testing; a social worker for psychotherapeutic strategies; another social worker to assist in obtaining social assistance; an addiction counselor for substance use disorder; another psychiatrist who monitors the administration of a single medication, like ketamine; and a pharmacist who approves the medication regimen. That’s several providers for the treatment of one patient.

As a forensic psychiatrist, I am often asked to review treatment plans of other providers. I am asked to comment on the appropriate nature of a given treatment. Often, insurance companies want to review the continued need for treatment or whether any treatment is warranted at all. Sometimes, employers want to review a treatment plan to ensure the safety of their employees. At times, courts will ask for a review and expectations from treatment of a defendant to assist in sentencing determinations. However, I have not yet been asked by anyone if the amount of care a patient is obtaining is too fragmented and without any clear leadership.

In our endless pursuit of medicalization and standardization of mental health, we have, especially in large systems, created specialization silos for the care of our patients. Many, if not most psychiatrists, do not participate in any psychotherapy; social workers and psychologists do not prescribe (for the most part); many substance abuse counselors only address sobriety and not other primary mental illness factors; and pharmacists cannot diagnose nor are they trained in psychosocial approaches. In many ways, we have defined participants not by what they do, but what they don’t do.

One also can be saddened by the enormous logistical complexity imposed on patients required to make numerous appointments, which can deprive them of time for recovery. However, my bigger concern is that the multiplicity of providers also permits the dissolution of accountability. In my experience, those large teams have an ability to deflect responsibility in ways that are unmatched by any single provider who cannot rely on putting the fault on someone else.

Sadly and ironically, those two parallel paradigms of mental illness and criminal care impose those problems on each other by averting any attempt at interception, a “no-intercept model.” Mental health programs will deny clients involved in the criminal justice system for requiring too much treatment, too little treatment, for lack of availability of one of the necessary providers, for requiring substance use treatment, or simply for being part of the criminal justice system. Accordingly, the legal system will fail to accept recommendations by mental health providers that mental health treatment is not paramount at this time and that the defendant would be better served by addressing his criminogenic risk factors. In response, the multitude of participants in the legal system will point to the mental health system for all answers.

Contrary to many if not most problems, I do not think that the solution lies somewhere in the middle, as this would require the five stages of the legal system to compromise with the nine hypothetical participants of the mental health system. I think that the solution lies in a resurgence of personal accountability and responsibility. For our part, as psychiatrists, we must accept that we are ultimately responsible for all levels of care. As a field, we are also responsible for educating the public and the legal system of our role and limitations in providing care as well as being available for providing such care. Correspondingly, the legal system is responsible for putting an adequate effort into diverting patients and having or obtaining adequate understanding of available and appropriate care for their defendants.
 

Dr. Badre is a forensic psychiatrist in San Diego and an expert in correctional mental health. He holds teaching positions at the University of California, San Diego, and the University of San Diego. He teaches medical education, psychopharmacology, ethics in psychiatry, and correctional care. Among his writings is chapter 7 in the new book “Critical Psychiatry: Controversies and Clinical Implications” (Springer, 2019).

In legal settings, the “sequential intercept model” for targeting people involved in the criminal justice system with mental illness has been proposed as an improvement for the status quo.

The model intends to divert individuals with mental illnesses at any one of five described stages in their journey through the legal system. In the first stage, a patient may be provided enough care in the community to never enter the criminal system. If that works, the patient may be diverted by first responders out of the legal system and back into treatment. Sequentially, throughout the remaining stages, the patient can be diverted by an attorney, the court, a presentencing correctional facility, the sentencing judge, a postsentencing correctional facility, or probation. The model rightfully encourages anyone in the continuum of care to take ownership of a situation and intervene.

I applaud the model for encouraging all participants to intervene in changing the course of our most challenging patients. However, I am reminded of the complexity of large systems trying to change. In practice, what I have seen is a series of half-hearted recommendations: Emergency responders who consider their role finished after giving a patient the number of the suicide hotline, attorneys who are satisfied by giving their clients an outdated list of community mental health clinics, judges who interpret their recommendations for treatment as a fait accompli, and correctional facilities that release patients with an absurdly short supply of medications and the address of an emergency room. I worry that by creating a model encouraging all to participate, we have just absolved ones who make any effort, even if inadequate.

In some ways, the sequential intercept model has similarities with modern mental health treatment teams. In many settings, a treatment team includes a series of providers who are sequentially involved in the life of a patient. A team can include a psychiatrist for psychopharmacology; a neuropsychologist for psychological testing; a social worker for psychotherapeutic strategies; another social worker to assist in obtaining social assistance; an addiction counselor for substance use disorder; another psychiatrist who monitors the administration of a single medication, like ketamine; and a pharmacist who approves the medication regimen. That’s several providers for the treatment of one patient.

As a forensic psychiatrist, I am often asked to review treatment plans of other providers. I am asked to comment on the appropriate nature of a given treatment. Often, insurance companies want to review the continued need for treatment or whether any treatment is warranted at all. Sometimes, employers want to review a treatment plan to ensure the safety of their employees. At times, courts will ask for a review and expectations from treatment of a defendant to assist in sentencing determinations. However, I have not yet been asked by anyone if the amount of care a patient is obtaining is too fragmented and without any clear leadership.

In our endless pursuit of medicalization and standardization of mental health, we have, especially in large systems, created specialization silos for the care of our patients. Many, if not most psychiatrists, do not participate in any psychotherapy; social workers and psychologists do not prescribe (for the most part); many substance abuse counselors only address sobriety and not other primary mental illness factors; and pharmacists cannot diagnose nor are they trained in psychosocial approaches. In many ways, we have defined participants not by what they do, but what they don’t do.

One also can be saddened by the enormous logistical complexity imposed on patients required to make numerous appointments, which can deprive them of time for recovery. However, my bigger concern is that the multiplicity of providers also permits the dissolution of accountability. In my experience, those large teams have an ability to deflect responsibility in ways that are unmatched by any single provider who cannot rely on putting the fault on someone else.

Sadly and ironically, those two parallel paradigms of mental illness and criminal care impose those problems on each other by averting any attempt at interception, a “no-intercept model.” Mental health programs will deny clients involved in the criminal justice system for requiring too much treatment, too little treatment, for lack of availability of one of the necessary providers, for requiring substance use treatment, or simply for being part of the criminal justice system. Accordingly, the legal system will fail to accept recommendations by mental health providers that mental health treatment is not paramount at this time and that the defendant would be better served by addressing his criminogenic risk factors. In response, the multitude of participants in the legal system will point to the mental health system for all answers.

Contrary to many if not most problems, I do not think that the solution lies somewhere in the middle, as this would require the five stages of the legal system to compromise with the nine hypothetical participants of the mental health system. I think that the solution lies in a resurgence of personal accountability and responsibility. For our part, as psychiatrists, we must accept that we are ultimately responsible for all levels of care. As a field, we are also responsible for educating the public and the legal system of our role and limitations in providing care as well as being available for providing such care. Correspondingly, the legal system is responsible for putting an adequate effort into diverting patients and having or obtaining adequate understanding of available and appropriate care for their defendants.
 

Dr. Badre is a forensic psychiatrist in San Diego and an expert in correctional mental health. He holds teaching positions at the University of California, San Diego, and the University of San Diego. He teaches medical education, psychopharmacology, ethics in psychiatry, and correctional care. Among his writings is chapter 7 in the new book “Critical Psychiatry: Controversies and Clinical Implications” (Springer, 2019).

As I write, I imagine readers groaning at yet another measles story. But in early November 2019, in Portland, Oregon, Judy Guzman-Cottrill, DO, recently was groaning at yet another measles case.

Bilanol/iStock/Getty Images 

Dr. Guzman-Cottrill, a pediatric infectious diseases specialist at Doernbecher Children’s Hospital, recently shared details provided by the local health department:

An unimmunized child developed measles while traveling outside the county. The child may have exposed others at Portland International Airport, a medical center in Vancouver, and potentially at another children’s hospital in the area.

As of Nov. 7, 2019, 1,261 cases of measles from 31 states had been reported to the Centers for Disease Control and Prevention – more cases in a single year since 1992. The case in Portland added at least one to that total, although public officials warned that additional cases could occur Nov. 18th through Dec. 9 (given the incubation period). Like the child in Oregon, most of the individuals who developed measles nationwide in 2019 were unimmunized. At press time, from Jan. 1 to Dec. 5, 2019, 1,276 individual cases of measles have been confirmed in 31 states; CDC released measles reports monthly.

The reasons for refusal of measles vaccine vary, but historically, some parents have made a calculated risk. Measles is rare. Most children are vaccinated. My child will be protected by herd immunity. In some communities, that is no longer true, as we have seen in 2019.

Other parents have decided – erroneously – that measles infection is less risky than measles vaccine. We need to be able to tell them the facts. Thirty percent of individuals who contract measles will develop at least one complication, according to the Centers for Disease Control and Prevention. One in four will be hospitalized. While death from acute measles infection is uncommon, children remain at risk for sequelae months or years after the initial infection.

For example, measles is known to suppress the immune system, an effect that lasts for months or years after the initial infection. Practically, this means that once a child recovers from acute measles infection, he or she has an increased susceptibility to other infections that may last for years. Two studies published late in 2019 described the immune “amnesia” that occurs following measles infection. Essentially, the immune system forgets how to fight other pathogens, leaving children vulnerable to potentially life-threatening infections.

Michael Mina, MD, of the Harvard T.H. Chan School of Public Health, Boston, and colleagues measured the effects of measles infection on the immune system by studying blood samples taken from 77 unimmunized children in the Netherlands before and after measles infection.¹ Two months after recovery from mild measles, children had lost a median of 33 % (range, 12%-73%) of preexisting antibodies against a range of common viruses and bacteria. The median loss was 40% after severe measles (range 11% to 62%). Similar changes were not observed after measles vaccine.

A second group of researchers led by Velislava N. Petrova, PhD, of the Wellcome Sanger Institute in Cambridge, England, investigated genetic changes in 26 unvaccinated children from the Netherlands who previously had measles. They found that measles infection reduced the diversity of immune cells available to recognize and fight infections and depleted memory B cells, essentially returning the immune to a more immature state.²

Parents also need to know that children who develop measles are at risk for noninfectious complications. Subacute sclerosing panencephalitis (SSPE) is a fatal neurodegenerative disease that occurs years after initial measles infection.

Yes, SSPE is a rare, but it is not as rare as we once thought. In 2017, investigators in California described 17 cases of SSPE identified in that state between 1998 and 2005.³ The incidence of SSPE was 1 in 1,367 for children less than 5 years at the time of measles infection and 1 in 609 for children less than 12 months when they contracted the virus.

Dr. Guzman-Cottrill has seen a case of SSPE, and she hopes to never see another one. “He had been a healthy 11-year-old boy,” she recalled. “He played soccer and basketball and did well in school.” In the beginning, his symptoms were insidious and nonspecific, Dr. Guzman-Cottrill and colleagues wrote in a 2016 issue of Morbidity and Mortality Weekly Report.⁴ He started to struggle in school. He dozed off in the middle of meals. He started to drop things. Over a 4-month period, the boy developed progressive spasticity, became unable to eat or drink, and could no longer recognize or communicate with his family. “That’s when I met him,” Dr. Guzman-Cottrill said. “It was heartbreaking, and there was very little we could do for him except give the family a diagnosis. He eventually died in hospice care, nearly 4 years after his symptoms began.”

The boy had been infected with measles at 1 year of age while living in the Philippines. Dr. Guzman-Cottrill emphasized that this family had not refused measles immunization. The child had received a measles vaccine at 8 months of age, but a single vaccine at such a young age wasn’t enough to protect him.

We can hope for change in 2020, including improved immunization rates and a decline in measles cases. If that happens, measles will no longer be a hot topic in the news. We’ll likely never know what happens to the children infected in 2019, those who are facing the current cold and flu season with impaired immune systems. A decade or more will pass before we’ll know if anyone develops SSPE. For now, all we can do is wait … and worry.

Dr. Bryant is a pediatrician specializing in infectious diseases at the University of Louisville, Ky., and Norton Children’s Hospital, also in Louisville. Dr. Bryant had no relevant financial disclosures. Email her at [email protected].
 

References

1. Science. 2019 Nov 1;366:599-606.

2. Science Immunology. 2019 Nov 1;4:eaay6125.

3. Clin Infect Dis. 2017 Jul 15;65(2):226-32.

4. MMWR Morb Mortal Wkly Rep. 2016 Jan 15;65(1):10-11.

As I write, I imagine readers groaning at yet another measles story. But in early November 2019, in Portland, Oregon, Judy Guzman-Cottrill, DO, recently was groaning at yet another measles case.

Bilanol/iStock/Getty Images 

Dr. Guzman-Cottrill, a pediatric infectious diseases specialist at Doernbecher Children’s Hospital, recently shared details provided by the local health department:

An unimmunized child developed measles while traveling outside the county. The child may have exposed others at Portland International Airport, a medical center in Vancouver, and potentially at another children’s hospital in the area.

As of Nov. 7, 2019, 1,261 cases of measles from 31 states had been reported to the Centers for Disease Control and Prevention – more cases in a single year since 1992. The case in Portland added at least one to that total, although public officials warned that additional cases could occur Nov. 18th through Dec. 9 (given the incubation period). Like the child in Oregon, most of the individuals who developed measles nationwide in 2019 were unimmunized. At press time, from Jan. 1 to Dec. 5, 2019, 1,276 individual cases of measles have been confirmed in 31 states; CDC released measles reports monthly.

The reasons for refusal of measles vaccine vary, but historically, some parents have made a calculated risk. Measles is rare. Most children are vaccinated. My child will be protected by herd immunity. In some communities, that is no longer true, as we have seen in 2019.

Other parents have decided – erroneously – that measles infection is less risky than measles vaccine. We need to be able to tell them the facts. Thirty percent of individuals who contract measles will develop at least one complication, according to the Centers for Disease Control and Prevention. One in four will be hospitalized. While death from acute measles infection is uncommon, children remain at risk for sequelae months or years after the initial infection.

For example, measles is known to suppress the immune system, an effect that lasts for months or years after the initial infection. Practically, this means that once a child recovers from acute measles infection, he or she has an increased susceptibility to other infections that may last for years. Two studies published late in 2019 described the immune “amnesia” that occurs following measles infection. Essentially, the immune system forgets how to fight other pathogens, leaving children vulnerable to potentially life-threatening infections.

Michael Mina, MD, of the Harvard T.H. Chan School of Public Health, Boston, and colleagues measured the effects of measles infection on the immune system by studying blood samples taken from 77 unimmunized children in the Netherlands before and after measles infection.¹ Two months after recovery from mild measles, children had lost a median of 33 % (range, 12%-73%) of preexisting antibodies against a range of common viruses and bacteria. The median loss was 40% after severe measles (range 11% to 62%). Similar changes were not observed after measles vaccine.

A second group of researchers led by Velislava N. Petrova, PhD, of the Wellcome Sanger Institute in Cambridge, England, investigated genetic changes in 26 unvaccinated children from the Netherlands who previously had measles. They found that measles infection reduced the diversity of immune cells available to recognize and fight infections and depleted memory B cells, essentially returning the immune to a more immature state.²

Parents also need to know that children who develop measles are at risk for noninfectious complications. Subacute sclerosing panencephalitis (SSPE) is a fatal neurodegenerative disease that occurs years after initial measles infection.

Yes, SSPE is a rare, but it is not as rare as we once thought. In 2017, investigators in California described 17 cases of SSPE identified in that state between 1998 and 2005.³ The incidence of SSPE was 1 in 1,367 for children less than 5 years at the time of measles infection and 1 in 609 for children less than 12 months when they contracted the virus.

Dr. Guzman-Cottrill has seen a case of SSPE, and she hopes to never see another one. “He had been a healthy 11-year-old boy,” she recalled. “He played soccer and basketball and did well in school.” In the beginning, his symptoms were insidious and nonspecific, Dr. Guzman-Cottrill and colleagues wrote in a 2016 issue of Morbidity and Mortality Weekly Report.⁴ He started to struggle in school. He dozed off in the middle of meals. He started to drop things. Over a 4-month period, the boy developed progressive spasticity, became unable to eat or drink, and could no longer recognize or communicate with his family. “That’s when I met him,” Dr. Guzman-Cottrill said. “It was heartbreaking, and there was very little we could do for him except give the family a diagnosis. He eventually died in hospice care, nearly 4 years after his symptoms began.”

The boy had been infected with measles at 1 year of age while living in the Philippines. Dr. Guzman-Cottrill emphasized that this family had not refused measles immunization. The child had received a measles vaccine at 8 months of age, but a single vaccine at such a young age wasn’t enough to protect him.

We can hope for change in 2020, including improved immunization rates and a decline in measles cases. If that happens, measles will no longer be a hot topic in the news. We’ll likely never know what happens to the children infected in 2019, those who are facing the current cold and flu season with impaired immune systems. A decade or more will pass before we’ll know if anyone develops SSPE. For now, all we can do is wait … and worry.

Dr. Bryant is a pediatrician specializing in infectious diseases at the University of Louisville, Ky., and Norton Children’s Hospital, also in Louisville. Dr. Bryant had no relevant financial disclosures. Email her at [email protected].
 

References

1. Science. 2019 Nov 1;366:599-606.

2. Science Immunology. 2019 Nov 1;4:eaay6125.

3. Clin Infect Dis. 2017 Jul 15;65(2):226-32.

4. MMWR Morb Mortal Wkly Rep. 2016 Jan 15;65(1):10-11.

As I write, I imagine readers groaning at yet another measles story. But in early November 2019, in Portland, Oregon, Judy Guzman-Cottrill, DO, recently was groaning at yet another measles case.

Bilanol/iStock/Getty Images 

Dr. Guzman-Cottrill, a pediatric infectious diseases specialist at Doernbecher Children’s Hospital, recently shared details provided by the local health department:

An unimmunized child developed measles while traveling outside the county. The child may have exposed others at Portland International Airport, a medical center in Vancouver, and potentially at another children’s hospital in the area.

As of Nov. 7, 2019, 1,261 cases of measles from 31 states had been reported to the Centers for Disease Control and Prevention – more cases in a single year since 1992. The case in Portland added at least one to that total, although public officials warned that additional cases could occur Nov. 18th through Dec. 9 (given the incubation period). Like the child in Oregon, most of the individuals who developed measles nationwide in 2019 were unimmunized. At press time, from Jan. 1 to Dec. 5, 2019, 1,276 individual cases of measles have been confirmed in 31 states; CDC released measles reports monthly.

The reasons for refusal of measles vaccine vary, but historically, some parents have made a calculated risk. Measles is rare. Most children are vaccinated. My child will be protected by herd immunity. In some communities, that is no longer true, as we have seen in 2019.

Other parents have decided – erroneously – that measles infection is less risky than measles vaccine. We need to be able to tell them the facts. Thirty percent of individuals who contract measles will develop at least one complication, according to the Centers for Disease Control and Prevention. One in four will be hospitalized. While death from acute measles infection is uncommon, children remain at risk for sequelae months or years after the initial infection.

For example, measles is known to suppress the immune system, an effect that lasts for months or years after the initial infection. Practically, this means that once a child recovers from acute measles infection, he or she has an increased susceptibility to other infections that may last for years. Two studies published late in 2019 described the immune “amnesia” that occurs following measles infection. Essentially, the immune system forgets how to fight other pathogens, leaving children vulnerable to potentially life-threatening infections.

Michael Mina, MD, of the Harvard T.H. Chan School of Public Health, Boston, and colleagues measured the effects of measles infection on the immune system by studying blood samples taken from 77 unimmunized children in the Netherlands before and after measles infection.¹ Two months after recovery from mild measles, children had lost a median of 33 % (range, 12%-73%) of preexisting antibodies against a range of common viruses and bacteria. The median loss was 40% after severe measles (range 11% to 62%). Similar changes were not observed after measles vaccine.

A second group of researchers led by Velislava N. Petrova, PhD, of the Wellcome Sanger Institute in Cambridge, England, investigated genetic changes in 26 unvaccinated children from the Netherlands who previously had measles. They found that measles infection reduced the diversity of immune cells available to recognize and fight infections and depleted memory B cells, essentially returning the immune to a more immature state.²

Parents also need to know that children who develop measles are at risk for noninfectious complications. Subacute sclerosing panencephalitis (SSPE) is a fatal neurodegenerative disease that occurs years after initial measles infection.

Yes, SSPE is a rare, but it is not as rare as we once thought. In 2017, investigators in California described 17 cases of SSPE identified in that state between 1998 and 2005.³ The incidence of SSPE was 1 in 1,367 for children less than 5 years at the time of measles infection and 1 in 609 for children less than 12 months when they contracted the virus.

Dr. Guzman-Cottrill has seen a case of SSPE, and she hopes to never see another one. “He had been a healthy 11-year-old boy,” she recalled. “He played soccer and basketball and did well in school.” In the beginning, his symptoms were insidious and nonspecific, Dr. Guzman-Cottrill and colleagues wrote in a 2016 issue of Morbidity and Mortality Weekly Report.⁴ He started to struggle in school. He dozed off in the middle of meals. He started to drop things. Over a 4-month period, the boy developed progressive spasticity, became unable to eat or drink, and could no longer recognize or communicate with his family. “That’s when I met him,” Dr. Guzman-Cottrill said. “It was heartbreaking, and there was very little we could do for him except give the family a diagnosis. He eventually died in hospice care, nearly 4 years after his symptoms began.”

The boy had been infected with measles at 1 year of age while living in the Philippines. Dr. Guzman-Cottrill emphasized that this family had not refused measles immunization. The child had received a measles vaccine at 8 months of age, but a single vaccine at such a young age wasn’t enough to protect him.

We can hope for change in 2020, including improved immunization rates and a decline in measles cases. If that happens, measles will no longer be a hot topic in the news. We’ll likely never know what happens to the children infected in 2019, those who are facing the current cold and flu season with impaired immune systems. A decade or more will pass before we’ll know if anyone develops SSPE. For now, all we can do is wait … and worry.

Dr. Bryant is a pediatrician specializing in infectious diseases at the University of Louisville, Ky., and Norton Children’s Hospital, also in Louisville. Dr. Bryant had no relevant financial disclosures. Email her at [email protected].
 

References

1. Science. 2019 Nov 1;366:599-606.

2. Science Immunology. 2019 Nov 1;4:eaay6125.

3. Clin Infect Dis. 2017 Jul 15;65(2):226-32.

4. MMWR Morb Mortal Wkly Rep. 2016 Jan 15;65(1):10-11.

ORLANDO – For the first time, there is a maintenance therapy for patients with acute myeloid leukemia (AML) in remission that can improve overall survival – a new oral formulation of an old drug, azacitidine, known as CC-486 (Celgene).

“Oral azacitidine represents a new therapeutic standard for patients with AML in remission,” said lead author Andrew H. Wei, MBBS, PhD, from the Alfred Hospital in Melbourne.

“It’s not too hard to get these patients into remission,” commented another expert. “The problem comes in keeping them in remission.”

Dr. Wei noted that standard treatment with intensive induction chemotherapy for AML induces complete remission (CR) in 60%-80% of patients aged 60 years or younger and in 40%-60% of patients aged 60 years or older.

However, the majority of patients who attain complete remission (CR) will eventually relapse, and relapse is the primary obstacle to long-term survival, he said.

Despite various attempts, there has been no success over the past 30 years in defining maintenance treatment for these patients, Dr. Wei said.

The new results suggest that oral azacitidine could be an effective maintenance therapy.

Dr. Wei presented the results at the 2019 annual meeting of the American Society of Hematology. They come from the QUAZAR AML-001 study, conducted in 472 patients with poor-risk AML in first remission.

The results show that CC-486 significantly improved outcomes, compared with placebo plus best supportive care, in terms of median overall survival (24.7 vs. 14.8 months) and median relapse-free survival (10.2 vs. 4.8 months).

The trial was funded by Celgene, which said it will be submitting the data for regulatory approval for the new oral formulation of azacitidine, CC-486.
 

Experts predict new standard of care

Experts approached for comment agreed that maintenance oral azacitidine will become the new standard of care for patients with AML in first remission.

“Unlike therapy for acute lymphoblastic leukemia, maintenance therapy has not been part of the treatment algorithm for AML patients in first remission,” Harry P. Erba, MD, PhD, director of the leukemia program at the Duke Cancer Institute, Durham, N.C., told Medscape Medical News.

He explained that trials for maintenance after first remission in AML have failed. Recently, Dr. Erba noted, the HOVON97 trial with injectable azacitidine demonstrated improvement in relapse-free survival, compared with observation for older AML patients achieving remission after induction therapy. “However, there was no improvement in overall survival,” he said.

“Remission in AML is short lived,” Dr. Erba said. Oral azacitidine represents the first maintenance therapy in AML that has shown both significant and clinically meaningful improvements in overall and relapse-free survival and will represent a new standard of care for patients with AML in remission, Dr. Erba said. “Maintenance oral azacitidine will be practice changing,” he predicted.

HOVON97 was a small study of injectable azacitidine used as maintenance therapy for 12 months, but it was slow to accrue and did not meet its accrual target.

“In HOVON97, at 12 months, only one third of patients received less than the 12 cycles of therapy,” Dr. Wei said. He explained that, with injectable azacitidine, patients have to come into the hospital/clinic for 7 days a month, 84 days a year. Oral azacitidine is more convenient as patients do not have to come into the clinic, he said.

Dr. Wei pointed out that about 40 patients in the QUAZAR study, which started in 2013, are still on maintenance therapy, with one patient now having received 80 cycles of therapy (approximately 7 years). “Long-term maintenance therapy with azacitidine is possible,” he said.

Another expert was also impressed by the new results. “This is an important clinical trial that addresses an unmet need in AML care,” said John Mascarenhas, MD, director of the Adult Leukemia Program and leader of clinical investigation within the myeloproliferative disorders program at the Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, New York.

“Older patients can often receive induction chemotherapy but frequently do not ultimately do well, as the disease relapses and survival is limited,” he explained.

“This large, randomized, double-blind, controlled study of intermediate- or poor-risk AML patients over the age of 55 years supports the use of maintenance oral azacitidine after initial remission to extend overall and relapse-free survival in older AML patients not eligible for transplant,” Dr. Mascarenhas said.

“This is still not a curative approach,” Dr. Wei said, but added that it prolongs relapse-free survival for older patients while maintaining a quality of life for as long as possible.
 

Study details

The QUAZAR phase 3 study enrolled patients with poor- or intermediate-risk cytogenetics who had an Eastern Cooperative Oncology Group performance status less than or equal to 3 and who had achieved CR or CR with incomplete count recovery (CRi) after induction therapy with or without consolidation therapy. In addition, patients were not candidates for stem cell transplants.

Patients had predominantly de novo AML (89%). Other baseline characteristics of note:

• 85% of patients had intermediate-risk and 15% had poor-risk cytogenetics
• 79% achieved CR and 21% achieved CRi after induction therapy
• 78% received at least one cycle of consolidation therapy
• 43% of patients had minimal residual disease (MRD)–positive disease

Patients were randomized to receive oral azacitidine 200 mg daily on days 1-14 of a repeat 28-day cycle (n = 278) or matching placebo (n = 274). Treatment was continued indefinitely until blast count was more than 15% or patients experienced unacceptable toxicity or went on to transplant.

At a median follow-up of over 41.2 months (3 years, 5 months), median overall survival was significantly longer for patients receiving oral azacitidine at 24.7 months versus 14.8 months for placebo (P less than .0009; hazard ratio, 0.69).

Relapse-free survival was also significantly prolonged, to 10.2 months for patients on oral azacitidine versus 4.8 months for placebo (HR, 0.65; P less than .0001).

Patients on oral azacitidine reported more grade 1-2 gastrointestinal adverse events, such as nausea (65% vs. 24% on placebo), vomiting (60% vs. 10%), and diarrhea (50% vs 22%), as well as more cytopenia. The most common grade 3-4 adverse events were neutropenia (41% with oral azacitidine vs. 24% on placebo), thrombocytopenia (23% vs. 22%), and anemia (14% vs. 13%).

Although Dr. Erba supported the use of oral azacitidine as maintenance therapy, he pointed out that it was hard to convince patients, especially older ones, to continue on maintenance therapy indefinitely. “The toxicities of continuing on a drug indefinitely are real issues,” he said, explaining that most elderly patients cannot cope with even grade 1-2 nausea, diarrhea, and vomiting over the long term.

But he noted that, regardless of the higher incidence of some adverse events with oral azacitidine, the health-related quality of life of patients on oral azacitidine was similar to those on placebo.
 

Awaiting longer follow-up

Both experts said that longer-term follow-up is needed.

“We need a longer follow-up to see how the curves plateau,” Dr. Erba said. He would also like to see a comparative analysis of the data in patients who are MRD negative versus those who are MRD positive.

“The final results of this study, including the impact of measurable residual disease on outcome in this setting, will potentially have practice-changing implications,” said Dr. Mascarenhas.

At the press conference, Dr. Wei pointed out that, based on the data from QUAZAR, oral azacitidine is likely to be evaluated in the frontline setting of AML. “The elderly make up about two-thirds of all AML patients, and oral azacitidine will be a better option than 7 days per month for chemotherapy treatment in the clinic,” he said. “Oral azacitidine in the future may also be the backbone for other combinations.”

The study was funded by Celgene.

Dr. Wei receives honoraria from AbbVie, Macrogenics, Pfizer, Astellas, Janssen, Servier, Celgene, Amgen, AstraZeneca, Novartis, and Genentech; is on the board of directors or serves on the advisory committees for AbbVie, Macrogenics, Pfizer, Astellas, Servier, Celgene, Amgen, Novartis, and Genentech; and receives research funding from AbbVie, Servier, Celgene, Amgen, AstraZeneca, and Novartis. As a former employee of the Walter and Eliza Hall Institute, Dr. Wei receives a fraction of its royalty stream related to venetoclax.

A partial list of Dr. Erba’s conflict of interest includes consulting with Agios, Novartis, Daiichi Sankyo, MacroGenics, Jazz Pharmaceuticals, Seattle Genetics, GlycoMimetics, Amgen, Pfizer, Celgene, AbbVie, Covance, Immunogen, Astellas Pharma, Incyte; being on the speakers bureau or receiving lecture fees from Agios, Novartis, MacroGenics, Jazz Pharmaceuticals, Celgene; receiving research funding from Novartis, Daiichi Sankyo, MacroGenics, GlycoMimetics, Celgene; being on the data and safety monitoring board of GlycoMimetics; and chairing independent review boards for several trials across several companies.
 

A version of this story originally appeared on Medscape.com.

ORLANDO – For the first time, there is a maintenance therapy for patients with acute myeloid leukemia (AML) in remission that can improve overall survival – a new oral formulation of an old drug, azacitidine, known as CC-486 (Celgene).

“Oral azacitidine represents a new therapeutic standard for patients with AML in remission,” said lead author Andrew H. Wei, MBBS, PhD, from the Alfred Hospital in Melbourne.

“It’s not too hard to get these patients into remission,” commented another expert. “The problem comes in keeping them in remission.”

Dr. Wei noted that standard treatment with intensive induction chemotherapy for AML induces complete remission (CR) in 60%-80% of patients aged 60 years or younger and in 40%-60% of patients aged 60 years or older.

However, the majority of patients who attain complete remission (CR) will eventually relapse, and relapse is the primary obstacle to long-term survival, he said.

Despite various attempts, there has been no success over the past 30 years in defining maintenance treatment for these patients, Dr. Wei said.

The new results suggest that oral azacitidine could be an effective maintenance therapy.

Dr. Wei presented the results at the 2019 annual meeting of the American Society of Hematology. They come from the QUAZAR AML-001 study, conducted in 472 patients with poor-risk AML in first remission.

The results show that CC-486 significantly improved outcomes, compared with placebo plus best supportive care, in terms of median overall survival (24.7 vs. 14.8 months) and median relapse-free survival (10.2 vs. 4.8 months).

The trial was funded by Celgene, which said it will be submitting the data for regulatory approval for the new oral formulation of azacitidine, CC-486.
 

Experts predict new standard of care

Experts approached for comment agreed that maintenance oral azacitidine will become the new standard of care for patients with AML in first remission.

“Unlike therapy for acute lymphoblastic leukemia, maintenance therapy has not been part of the treatment algorithm for AML patients in first remission,” Harry P. Erba, MD, PhD, director of the leukemia program at the Duke Cancer Institute, Durham, N.C., told Medscape Medical News.

He explained that trials for maintenance after first remission in AML have failed. Recently, Dr. Erba noted, the HOVON97 trial with injectable azacitidine demonstrated improvement in relapse-free survival, compared with observation for older AML patients achieving remission after induction therapy. “However, there was no improvement in overall survival,” he said.

“Remission in AML is short lived,” Dr. Erba said. Oral azacitidine represents the first maintenance therapy in AML that has shown both significant and clinically meaningful improvements in overall and relapse-free survival and will represent a new standard of care for patients with AML in remission, Dr. Erba said. “Maintenance oral azacitidine will be practice changing,” he predicted.

HOVON97 was a small study of injectable azacitidine used as maintenance therapy for 12 months, but it was slow to accrue and did not meet its accrual target.

“In HOVON97, at 12 months, only one third of patients received less than the 12 cycles of therapy,” Dr. Wei said. He explained that, with injectable azacitidine, patients have to come into the hospital/clinic for 7 days a month, 84 days a year. Oral azacitidine is more convenient as patients do not have to come into the clinic, he said.

Dr. Wei pointed out that about 40 patients in the QUAZAR study, which started in 2013, are still on maintenance therapy, with one patient now having received 80 cycles of therapy (approximately 7 years). “Long-term maintenance therapy with azacitidine is possible,” he said.

Another expert was also impressed by the new results. “This is an important clinical trial that addresses an unmet need in AML care,” said John Mascarenhas, MD, director of the Adult Leukemia Program and leader of clinical investigation within the myeloproliferative disorders program at the Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, New York.

“Older patients can often receive induction chemotherapy but frequently do not ultimately do well, as the disease relapses and survival is limited,” he explained.

“This large, randomized, double-blind, controlled study of intermediate- or poor-risk AML patients over the age of 55 years supports the use of maintenance oral azacitidine after initial remission to extend overall and relapse-free survival in older AML patients not eligible for transplant,” Dr. Mascarenhas said.

“This is still not a curative approach,” Dr. Wei said, but added that it prolongs relapse-free survival for older patients while maintaining a quality of life for as long as possible.
 

Study details

The QUAZAR phase 3 study enrolled patients with poor- or intermediate-risk cytogenetics who had an Eastern Cooperative Oncology Group performance status less than or equal to 3 and who had achieved CR or CR with incomplete count recovery (CRi) after induction therapy with or without consolidation therapy. In addition, patients were not candidates for stem cell transplants.

Patients had predominantly de novo AML (89%). Other baseline characteristics of note:

• 85% of patients had intermediate-risk and 15% had poor-risk cytogenetics
• 79% achieved CR and 21% achieved CRi after induction therapy
• 78% received at least one cycle of consolidation therapy
• 43% of patients had minimal residual disease (MRD)–positive disease

Patients were randomized to receive oral azacitidine 200 mg daily on days 1-14 of a repeat 28-day cycle (n = 278) or matching placebo (n = 274). Treatment was continued indefinitely until blast count was more than 15% or patients experienced unacceptable toxicity or went on to transplant.

At a median follow-up of over 41.2 months (3 years, 5 months), median overall survival was significantly longer for patients receiving oral azacitidine at 24.7 months versus 14.8 months for placebo (P less than .0009; hazard ratio, 0.69).

Relapse-free survival was also significantly prolonged, to 10.2 months for patients on oral azacitidine versus 4.8 months for placebo (HR, 0.65; P less than .0001).

Patients on oral azacitidine reported more grade 1-2 gastrointestinal adverse events, such as nausea (65% vs. 24% on placebo), vomiting (60% vs. 10%), and diarrhea (50% vs 22%), as well as more cytopenia. The most common grade 3-4 adverse events were neutropenia (41% with oral azacitidine vs. 24% on placebo), thrombocytopenia (23% vs. 22%), and anemia (14% vs. 13%).

Although Dr. Erba supported the use of oral azacitidine as maintenance therapy, he pointed out that it was hard to convince patients, especially older ones, to continue on maintenance therapy indefinitely. “The toxicities of continuing on a drug indefinitely are real issues,” he said, explaining that most elderly patients cannot cope with even grade 1-2 nausea, diarrhea, and vomiting over the long term.

But he noted that, regardless of the higher incidence of some adverse events with oral azacitidine, the health-related quality of life of patients on oral azacitidine was similar to those on placebo.
 

Awaiting longer follow-up

Both experts said that longer-term follow-up is needed.

“We need a longer follow-up to see how the curves plateau,” Dr. Erba said. He would also like to see a comparative analysis of the data in patients who are MRD negative versus those who are MRD positive.

“The final results of this study, including the impact of measurable residual disease on outcome in this setting, will potentially have practice-changing implications,” said Dr. Mascarenhas.

At the press conference, Dr. Wei pointed out that, based on the data from QUAZAR, oral azacitidine is likely to be evaluated in the frontline setting of AML. “The elderly make up about two-thirds of all AML patients, and oral azacitidine will be a better option than 7 days per month for chemotherapy treatment in the clinic,” he said. “Oral azacitidine in the future may also be the backbone for other combinations.”

The study was funded by Celgene.

Dr. Wei receives honoraria from AbbVie, Macrogenics, Pfizer, Astellas, Janssen, Servier, Celgene, Amgen, AstraZeneca, Novartis, and Genentech; is on the board of directors or serves on the advisory committees for AbbVie, Macrogenics, Pfizer, Astellas, Servier, Celgene, Amgen, Novartis, and Genentech; and receives research funding from AbbVie, Servier, Celgene, Amgen, AstraZeneca, and Novartis. As a former employee of the Walter and Eliza Hall Institute, Dr. Wei receives a fraction of its royalty stream related to venetoclax.

A partial list of Dr. Erba’s conflict of interest includes consulting with Agios, Novartis, Daiichi Sankyo, MacroGenics, Jazz Pharmaceuticals, Seattle Genetics, GlycoMimetics, Amgen, Pfizer, Celgene, AbbVie, Covance, Immunogen, Astellas Pharma, Incyte; being on the speakers bureau or receiving lecture fees from Agios, Novartis, MacroGenics, Jazz Pharmaceuticals, Celgene; receiving research funding from Novartis, Daiichi Sankyo, MacroGenics, GlycoMimetics, Celgene; being on the data and safety monitoring board of GlycoMimetics; and chairing independent review boards for several trials across several companies.
 

A version of this story originally appeared on Medscape.com.

ORLANDO – For the first time, there is a maintenance therapy for patients with acute myeloid leukemia (AML) in remission that can improve overall survival – a new oral formulation of an old drug, azacitidine, known as CC-486 (Celgene).

“Oral azacitidine represents a new therapeutic standard for patients with AML in remission,” said lead author Andrew H. Wei, MBBS, PhD, from the Alfred Hospital in Melbourne.

“It’s not too hard to get these patients into remission,” commented another expert. “The problem comes in keeping them in remission.”

Dr. Wei noted that standard treatment with intensive induction chemotherapy for AML induces complete remission (CR) in 60%-80% of patients aged 60 years or younger and in 40%-60% of patients aged 60 years or older.

However, the majority of patients who attain complete remission (CR) will eventually relapse, and relapse is the primary obstacle to long-term survival, he said.

Despite various attempts, there has been no success over the past 30 years in defining maintenance treatment for these patients, Dr. Wei said.

The new results suggest that oral azacitidine could be an effective maintenance therapy.

Dr. Wei presented the results at the 2019 annual meeting of the American Society of Hematology. They come from the QUAZAR AML-001 study, conducted in 472 patients with poor-risk AML in first remission.

The results show that CC-486 significantly improved outcomes, compared with placebo plus best supportive care, in terms of median overall survival (24.7 vs. 14.8 months) and median relapse-free survival (10.2 vs. 4.8 months).

The trial was funded by Celgene, which said it will be submitting the data for regulatory approval for the new oral formulation of azacitidine, CC-486.
 

Experts predict new standard of care

Experts approached for comment agreed that maintenance oral azacitidine will become the new standard of care for patients with AML in first remission.

“Unlike therapy for acute lymphoblastic leukemia, maintenance therapy has not been part of the treatment algorithm for AML patients in first remission,” Harry P. Erba, MD, PhD, director of the leukemia program at the Duke Cancer Institute, Durham, N.C., told Medscape Medical News.

He explained that trials for maintenance after first remission in AML have failed. Recently, Dr. Erba noted, the HOVON97 trial with injectable azacitidine demonstrated improvement in relapse-free survival, compared with observation for older AML patients achieving remission after induction therapy. “However, there was no improvement in overall survival,” he said.

“Remission in AML is short lived,” Dr. Erba said. Oral azacitidine represents the first maintenance therapy in AML that has shown both significant and clinically meaningful improvements in overall and relapse-free survival and will represent a new standard of care for patients with AML in remission, Dr. Erba said. “Maintenance oral azacitidine will be practice changing,” he predicted.

HOVON97 was a small study of injectable azacitidine used as maintenance therapy for 12 months, but it was slow to accrue and did not meet its accrual target.

“In HOVON97, at 12 months, only one third of patients received less than the 12 cycles of therapy,” Dr. Wei said. He explained that, with injectable azacitidine, patients have to come into the hospital/clinic for 7 days a month, 84 days a year. Oral azacitidine is more convenient as patients do not have to come into the clinic, he said.

Dr. Wei pointed out that about 40 patients in the QUAZAR study, which started in 2013, are still on maintenance therapy, with one patient now having received 80 cycles of therapy (approximately 7 years). “Long-term maintenance therapy with azacitidine is possible,” he said.

Another expert was also impressed by the new results. “This is an important clinical trial that addresses an unmet need in AML care,” said John Mascarenhas, MD, director of the Adult Leukemia Program and leader of clinical investigation within the myeloproliferative disorders program at the Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, New York.

“Older patients can often receive induction chemotherapy but frequently do not ultimately do well, as the disease relapses and survival is limited,” he explained.

“This large, randomized, double-blind, controlled study of intermediate- or poor-risk AML patients over the age of 55 years supports the use of maintenance oral azacitidine after initial remission to extend overall and relapse-free survival in older AML patients not eligible for transplant,” Dr. Mascarenhas said.

“This is still not a curative approach,” Dr. Wei said, but added that it prolongs relapse-free survival for older patients while maintaining a quality of life for as long as possible.
 

Study details

The QUAZAR phase 3 study enrolled patients with poor- or intermediate-risk cytogenetics who had an Eastern Cooperative Oncology Group performance status less than or equal to 3 and who had achieved CR or CR with incomplete count recovery (CRi) after induction therapy with or without consolidation therapy. In addition, patients were not candidates for stem cell transplants.

Patients had predominantly de novo AML (89%). Other baseline characteristics of note:

• 85% of patients had intermediate-risk and 15% had poor-risk cytogenetics
• 79% achieved CR and 21% achieved CRi after induction therapy
• 78% received at least one cycle of consolidation therapy
• 43% of patients had minimal residual disease (MRD)–positive disease

Patients were randomized to receive oral azacitidine 200 mg daily on days 1-14 of a repeat 28-day cycle (n = 278) or matching placebo (n = 274). Treatment was continued indefinitely until blast count was more than 15% or patients experienced unacceptable toxicity or went on to transplant.

At a median follow-up of over 41.2 months (3 years, 5 months), median overall survival was significantly longer for patients receiving oral azacitidine at 24.7 months versus 14.8 months for placebo (P less than .0009; hazard ratio, 0.69).

Relapse-free survival was also significantly prolonged, to 10.2 months for patients on oral azacitidine versus 4.8 months for placebo (HR, 0.65; P less than .0001).

Patients on oral azacitidine reported more grade 1-2 gastrointestinal adverse events, such as nausea (65% vs. 24% on placebo), vomiting (60% vs. 10%), and diarrhea (50% vs 22%), as well as more cytopenia. The most common grade 3-4 adverse events were neutropenia (41% with oral azacitidine vs. 24% on placebo), thrombocytopenia (23% vs. 22%), and anemia (14% vs. 13%).

Although Dr. Erba supported the use of oral azacitidine as maintenance therapy, he pointed out that it was hard to convince patients, especially older ones, to continue on maintenance therapy indefinitely. “The toxicities of continuing on a drug indefinitely are real issues,” he said, explaining that most elderly patients cannot cope with even grade 1-2 nausea, diarrhea, and vomiting over the long term.

But he noted that, regardless of the higher incidence of some adverse events with oral azacitidine, the health-related quality of life of patients on oral azacitidine was similar to those on placebo.
 

Awaiting longer follow-up

Both experts said that longer-term follow-up is needed.

“We need a longer follow-up to see how the curves plateau,” Dr. Erba said. He would also like to see a comparative analysis of the data in patients who are MRD negative versus those who are MRD positive.

“The final results of this study, including the impact of measurable residual disease on outcome in this setting, will potentially have practice-changing implications,” said Dr. Mascarenhas.

At the press conference, Dr. Wei pointed out that, based on the data from QUAZAR, oral azacitidine is likely to be evaluated in the frontline setting of AML. “The elderly make up about two-thirds of all AML patients, and oral azacitidine will be a better option than 7 days per month for chemotherapy treatment in the clinic,” he said. “Oral azacitidine in the future may also be the backbone for other combinations.”

The study was funded by Celgene.

Dr. Wei receives honoraria from AbbVie, Macrogenics, Pfizer, Astellas, Janssen, Servier, Celgene, Amgen, AstraZeneca, Novartis, and Genentech; is on the board of directors or serves on the advisory committees for AbbVie, Macrogenics, Pfizer, Astellas, Servier, Celgene, Amgen, Novartis, and Genentech; and receives research funding from AbbVie, Servier, Celgene, Amgen, AstraZeneca, and Novartis. As a former employee of the Walter and Eliza Hall Institute, Dr. Wei receives a fraction of its royalty stream related to venetoclax.

A partial list of Dr. Erba’s conflict of interest includes consulting with Agios, Novartis, Daiichi Sankyo, MacroGenics, Jazz Pharmaceuticals, Seattle Genetics, GlycoMimetics, Amgen, Pfizer, Celgene, AbbVie, Covance, Immunogen, Astellas Pharma, Incyte; being on the speakers bureau or receiving lecture fees from Agios, Novartis, MacroGenics, Jazz Pharmaceuticals, Celgene; receiving research funding from Novartis, Daiichi Sankyo, MacroGenics, GlycoMimetics, Celgene; being on the data and safety monitoring board of GlycoMimetics; and chairing independent review boards for several trials across several companies.
 

A version of this story originally appeared on Medscape.com.

LOS ANGELES – Until the recent approval of liraglutide for the treatment of children and adolescents with type 2 diabetes, investigators like Sonia Caprio, MD, were at their wits’ end watching the beta-cell function of their patients decline on metformin treatment.

Doug Brunk/MDedge News

“The kids were not doing well. It was like they were being treated with water,” Dr. Caprio, a pediatric endocrinologist at Yale University, New Haven, Conn., said at the annual World Congress on Insulin Resistance, Diabetes and Cardiovascular Disease.

For example, in the NIH-funded TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) study that began enrollment in 2004, 699 patients aged between 10 and 17 years and with type 2 diabetes were treated with metformin (1,000 mg, twice daily) to attain a glycated hemoglobin level of less than 8% and were then randomly assigned to continued treatment with metformin alone or to metformin combined with rosiglitazone (4 mg, twice a day) or a lifestyle-intervention program that focused on weight loss through modifying eating and activity behaviors (N Engl J Med. 2012;366:2247-56).

Over the course of 11 months, the researchers found that 46% of the children were failing treatment. “The worst arm was the metformin arm,” said Dr. Caprio, who was involved with the study. “Kids were not responding to the drug at all. About 52% of children failed to do better using metformin – a classic drug that we all start kids on when we diagnose them with type 2 diabetes.”

Findings from a follow-up study, TODAY2, showed that these young patients were prone to serious diabetes-related events, such as heart attacks, chronic kidney disease, retinal disease, neuropathy, and complications in the offspring of pregnancies.

In addition, results from the RISE (Restoring Insulin Secretion) Pediatric Medication Study found that, in youth with impaired glucose tolerance or recently diagnosed type 2 diabetes, neither 3 months of insulin glargine followed by 9 months of metformin nor 12 months of metformin alone halted the progressive deterioration of beta-cell function (Diabetes Care. 2018 Aug; 41[8]:1717-25).

“The uniqueness of RISE is that we employed very sophisticated techniques to measure insulin secretion and sensitivity while they were being treated with these usual drugs,” said Dr. Caprio, who was one of the study investigators. “The beta cell is unresponsive to metformin and other treatments. The question is, why?”

Despite these findings, 2018 consensus guidelines from the American Diabetes Association on the evaluation and management of youth-onset diabetes (Diabetes Care. 2018;41:2648-68) call for the administration of metformin twice daily in youth with new-onset diabetes who have a hemoglobin A_1c (HbA_1c) level of less than 8.5%. “I argue that is not the way. We need better ways to treat [these patients] because they are moving fast to having complications,” she said.

Enter the Ellipse Trial, a pivotal multicenter, randomized study that evaluated the effect of the glucagonlike peptide-1 receptor agonist liraglutide in children and adolescents with type 2 diabetes (N Engl J Med. 2019;381:637-46).

Researchers, led by William V. Tamborlane, MD, chief of Yale Medicine Pediatric Endocrinology, also in New Haven, randomized 135 patients to one of two arms: 66 to subcutaneous liraglutide (up to 1.8 mg/day) and 69 to placebo for a 26-week, double-blind period, followed by a 26-week open-label extension period. All patients received metformin during the trial. More than half of the study participants (62%) were female, the mean age was 15 years, 65% were white, the mean body mass index was 33.9 kg/m², their mean fasting glucose was 8.4 mmol/L, and their mean HbA_1c was 7.8%.

At 26 weeks, the mean glycated hemoglobin level had decreased by 0.64 percentage points with liraglutide and increased by 0.42 percentage points with placebo, for an estimated treatment difference of −1.06 percentage points (P less than .001). By 52 weeks, the difference increased to −1.30 percentage points.

“There was also a significant drop in BMI z score in patients treated with liraglutide, which is important,” Dr. Caprio said. “This medication is having an impact on weight, which is a key driver of the onset of type 2 diabetes in youth. This is a remarkable achievement because weight loss is hard to achieve in obese adolescents, as we showed in the TODAY study.”

The number of adverse events reported by patients was similar in the treatment and placebo groups (85% and 81%, respectively), but the overall rates of adverse events and gastrointestinal adverse events were higher with liraglutide.

“I use liraglutide just for weight reduction because I mainly see a lot of kids with obesity. Many kids are not responding because of the GI effects of this drug. I think the weight loss could have been better had the investigators moved to a dose of 1.8 mg, which we use in adults.”

A fasting plasma glucose of 6.1 mmol/L was the primary reason for participants remaining on a lower dose of liraglutide, she said. At the same time, liraglutide concentration data indicated a high rate of noncompliance, which was expected in this population. “That’s a big problem we face with children,” Dr. Caprio said. “Some of them are not constantly taking the medication. They skip doses a lot. But that happens with patients in this age group.”

“Finally, we have something else to help children and teenagers to delay the complications we are seeing,” Dr. Caprio said. “To me, I think this is a new era. I have hope. It will be interesting to see whether liraglutide and perhaps SGLT2 [sodium-glucose transporter 2] inhibitors can delay the onset of type 2 diabetes in children. In my view, we will be doing this with drugs. I don’t think the weight loss [concerns are] going to go away without medication, unfortunately.”

Dr. Caprio reported having no financial disclosures.

LOS ANGELES – Until the recent approval of liraglutide for the treatment of children and adolescents with type 2 diabetes, investigators like Sonia Caprio, MD, were at their wits’ end watching the beta-cell function of their patients decline on metformin treatment.

Doug Brunk/MDedge News

“The kids were not doing well. It was like they were being treated with water,” Dr. Caprio, a pediatric endocrinologist at Yale University, New Haven, Conn., said at the annual World Congress on Insulin Resistance, Diabetes and Cardiovascular Disease.

For example, in the NIH-funded TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) study that began enrollment in 2004, 699 patients aged between 10 and 17 years and with type 2 diabetes were treated with metformin (1,000 mg, twice daily) to attain a glycated hemoglobin level of less than 8% and were then randomly assigned to continued treatment with metformin alone or to metformin combined with rosiglitazone (4 mg, twice a day) or a lifestyle-intervention program that focused on weight loss through modifying eating and activity behaviors (N Engl J Med. 2012;366:2247-56).

Over the course of 11 months, the researchers found that 46% of the children were failing treatment. “The worst arm was the metformin arm,” said Dr. Caprio, who was involved with the study. “Kids were not responding to the drug at all. About 52% of children failed to do better using metformin – a classic drug that we all start kids on when we diagnose them with type 2 diabetes.”

Findings from a follow-up study, TODAY2, showed that these young patients were prone to serious diabetes-related events, such as heart attacks, chronic kidney disease, retinal disease, neuropathy, and complications in the offspring of pregnancies.

In addition, results from the RISE (Restoring Insulin Secretion) Pediatric Medication Study found that, in youth with impaired glucose tolerance or recently diagnosed type 2 diabetes, neither 3 months of insulin glargine followed by 9 months of metformin nor 12 months of metformin alone halted the progressive deterioration of beta-cell function (Diabetes Care. 2018 Aug; 41[8]:1717-25).

“The uniqueness of RISE is that we employed very sophisticated techniques to measure insulin secretion and sensitivity while they were being treated with these usual drugs,” said Dr. Caprio, who was one of the study investigators. “The beta cell is unresponsive to metformin and other treatments. The question is, why?”

Despite these findings, 2018 consensus guidelines from the American Diabetes Association on the evaluation and management of youth-onset diabetes (Diabetes Care. 2018;41:2648-68) call for the administration of metformin twice daily in youth with new-onset diabetes who have a hemoglobin A_1c (HbA_1c) level of less than 8.5%. “I argue that is not the way. We need better ways to treat [these patients] because they are moving fast to having complications,” she said.

Enter the Ellipse Trial, a pivotal multicenter, randomized study that evaluated the effect of the glucagonlike peptide-1 receptor agonist liraglutide in children and adolescents with type 2 diabetes (N Engl J Med. 2019;381:637-46).

Researchers, led by William V. Tamborlane, MD, chief of Yale Medicine Pediatric Endocrinology, also in New Haven, randomized 135 patients to one of two arms: 66 to subcutaneous liraglutide (up to 1.8 mg/day) and 69 to placebo for a 26-week, double-blind period, followed by a 26-week open-label extension period. All patients received metformin during the trial. More than half of the study participants (62%) were female, the mean age was 15 years, 65% were white, the mean body mass index was 33.9 kg/m², their mean fasting glucose was 8.4 mmol/L, and their mean HbA_1c was 7.8%.

At 26 weeks, the mean glycated hemoglobin level had decreased by 0.64 percentage points with liraglutide and increased by 0.42 percentage points with placebo, for an estimated treatment difference of −1.06 percentage points (P less than .001). By 52 weeks, the difference increased to −1.30 percentage points.

“There was also a significant drop in BMI z score in patients treated with liraglutide, which is important,” Dr. Caprio said. “This medication is having an impact on weight, which is a key driver of the onset of type 2 diabetes in youth. This is a remarkable achievement because weight loss is hard to achieve in obese adolescents, as we showed in the TODAY study.”

The number of adverse events reported by patients was similar in the treatment and placebo groups (85% and 81%, respectively), but the overall rates of adverse events and gastrointestinal adverse events were higher with liraglutide.

“I use liraglutide just for weight reduction because I mainly see a lot of kids with obesity. Many kids are not responding because of the GI effects of this drug. I think the weight loss could have been better had the investigators moved to a dose of 1.8 mg, which we use in adults.”

A fasting plasma glucose of 6.1 mmol/L was the primary reason for participants remaining on a lower dose of liraglutide, she said. At the same time, liraglutide concentration data indicated a high rate of noncompliance, which was expected in this population. “That’s a big problem we face with children,” Dr. Caprio said. “Some of them are not constantly taking the medication. They skip doses a lot. But that happens with patients in this age group.”

“Finally, we have something else to help children and teenagers to delay the complications we are seeing,” Dr. Caprio said. “To me, I think this is a new era. I have hope. It will be interesting to see whether liraglutide and perhaps SGLT2 [sodium-glucose transporter 2] inhibitors can delay the onset of type 2 diabetes in children. In my view, we will be doing this with drugs. I don’t think the weight loss [concerns are] going to go away without medication, unfortunately.”

Dr. Caprio reported having no financial disclosures.

LOS ANGELES – Until the recent approval of liraglutide for the treatment of children and adolescents with type 2 diabetes, investigators like Sonia Caprio, MD, were at their wits’ end watching the beta-cell function of their patients decline on metformin treatment.

Doug Brunk/MDedge News

“The kids were not doing well. It was like they were being treated with water,” Dr. Caprio, a pediatric endocrinologist at Yale University, New Haven, Conn., said at the annual World Congress on Insulin Resistance, Diabetes and Cardiovascular Disease.

For example, in the NIH-funded TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) study that began enrollment in 2004, 699 patients aged between 10 and 17 years and with type 2 diabetes were treated with metformin (1,000 mg, twice daily) to attain a glycated hemoglobin level of less than 8% and were then randomly assigned to continued treatment with metformin alone or to metformin combined with rosiglitazone (4 mg, twice a day) or a lifestyle-intervention program that focused on weight loss through modifying eating and activity behaviors (N Engl J Med. 2012;366:2247-56).

Over the course of 11 months, the researchers found that 46% of the children were failing treatment. “The worst arm was the metformin arm,” said Dr. Caprio, who was involved with the study. “Kids were not responding to the drug at all. About 52% of children failed to do better using metformin – a classic drug that we all start kids on when we diagnose them with type 2 diabetes.”

Findings from a follow-up study, TODAY2, showed that these young patients were prone to serious diabetes-related events, such as heart attacks, chronic kidney disease, retinal disease, neuropathy, and complications in the offspring of pregnancies.

In addition, results from the RISE (Restoring Insulin Secretion) Pediatric Medication Study found that, in youth with impaired glucose tolerance or recently diagnosed type 2 diabetes, neither 3 months of insulin glargine followed by 9 months of metformin nor 12 months of metformin alone halted the progressive deterioration of beta-cell function (Diabetes Care. 2018 Aug; 41[8]:1717-25).

“The uniqueness of RISE is that we employed very sophisticated techniques to measure insulin secretion and sensitivity while they were being treated with these usual drugs,” said Dr. Caprio, who was one of the study investigators. “The beta cell is unresponsive to metformin and other treatments. The question is, why?”

Despite these findings, 2018 consensus guidelines from the American Diabetes Association on the evaluation and management of youth-onset diabetes (Diabetes Care. 2018;41:2648-68) call for the administration of metformin twice daily in youth with new-onset diabetes who have a hemoglobin A_1c (HbA_1c) level of less than 8.5%. “I argue that is not the way. We need better ways to treat [these patients] because they are moving fast to having complications,” she said.

Enter the Ellipse Trial, a pivotal multicenter, randomized study that evaluated the effect of the glucagonlike peptide-1 receptor agonist liraglutide in children and adolescents with type 2 diabetes (N Engl J Med. 2019;381:637-46).

Researchers, led by William V. Tamborlane, MD, chief of Yale Medicine Pediatric Endocrinology, also in New Haven, randomized 135 patients to one of two arms: 66 to subcutaneous liraglutide (up to 1.8 mg/day) and 69 to placebo for a 26-week, double-blind period, followed by a 26-week open-label extension period. All patients received metformin during the trial. More than half of the study participants (62%) were female, the mean age was 15 years, 65% were white, the mean body mass index was 33.9 kg/m², their mean fasting glucose was 8.4 mmol/L, and their mean HbA_1c was 7.8%.

At 26 weeks, the mean glycated hemoglobin level had decreased by 0.64 percentage points with liraglutide and increased by 0.42 percentage points with placebo, for an estimated treatment difference of −1.06 percentage points (P less than .001). By 52 weeks, the difference increased to −1.30 percentage points.

“There was also a significant drop in BMI z score in patients treated with liraglutide, which is important,” Dr. Caprio said. “This medication is having an impact on weight, which is a key driver of the onset of type 2 diabetes in youth. This is a remarkable achievement because weight loss is hard to achieve in obese adolescents, as we showed in the TODAY study.”

The number of adverse events reported by patients was similar in the treatment and placebo groups (85% and 81%, respectively), but the overall rates of adverse events and gastrointestinal adverse events were higher with liraglutide.

“I use liraglutide just for weight reduction because I mainly see a lot of kids with obesity. Many kids are not responding because of the GI effects of this drug. I think the weight loss could have been better had the investigators moved to a dose of 1.8 mg, which we use in adults.”

A fasting plasma glucose of 6.1 mmol/L was the primary reason for participants remaining on a lower dose of liraglutide, she said. At the same time, liraglutide concentration data indicated a high rate of noncompliance, which was expected in this population. “That’s a big problem we face with children,” Dr. Caprio said. “Some of them are not constantly taking the medication. They skip doses a lot. But that happens with patients in this age group.”

“Finally, we have something else to help children and teenagers to delay the complications we are seeing,” Dr. Caprio said. “To me, I think this is a new era. I have hope. It will be interesting to see whether liraglutide and perhaps SGLT2 [sodium-glucose transporter 2] inhibitors can delay the onset of type 2 diabetes in children. In my view, we will be doing this with drugs. I don’t think the weight loss [concerns are] going to go away without medication, unfortunately.”

Dr. Caprio reported having no financial disclosures.

Investigators conducted a survey study of 214 patients with dermatofibrosarcoma protuberans (DFSP) or their family members using in part existing Facebook patient support groups (FBSG) to recruit respondents. They found the approach provides a “powerful” tool to collect relevant disease information from large numbers of patients with rare diseases.

A team of medical practitioners and patients developed the multiple-choice survey, and after testing the survey twice, posted a survey announcement on FBSGs for DFSP. The survey was live for 3 weeks in 2015. The investigators rapidly collected disease statistics, including information on recurrence, metastasis, surgical outcomes, diagnostic delay, and more, suggesting that FBSGs are useful medical research tools.

One hundred ninety-nine respondents were patients and 15 were family members. The respondents reported a median of 4 years to receive a correct diagnosis after noticing a lesion, ranging from less than 1 year to 42 years. About half the patients (52.3%) believed they received a misdiagnosis at some point, either from a dermatologist, primary care clinician, or another type of physician. Patients first noticed DFSP at a median age of 29.6 years. Many of their lesions appeared initially as flat plaques that eventually became protuberant. Because of this disconnect between the disease name and its clinical presentation, the investigators proposed the alternative term, dermatofibrosarcoma, often protuberant, be adopted. The investigators concluded that “FBSGs appear to be powerful tools to synergize effective and rapid research collaborations with large numbers of international patients with rare disease.” TSJ

Investigators conducted a survey study of 214 patients with dermatofibrosarcoma protuberans (DFSP) or their family members using in part existing Facebook patient support groups (FBSG) to recruit respondents. They found the approach provides a “powerful” tool to collect relevant disease information from large numbers of patients with rare diseases.

A team of medical practitioners and patients developed the multiple-choice survey, and after testing the survey twice, posted a survey announcement on FBSGs for DFSP. The survey was live for 3 weeks in 2015. The investigators rapidly collected disease statistics, including information on recurrence, metastasis, surgical outcomes, diagnostic delay, and more, suggesting that FBSGs are useful medical research tools.

One hundred ninety-nine respondents were patients and 15 were family members. The respondents reported a median of 4 years to receive a correct diagnosis after noticing a lesion, ranging from less than 1 year to 42 years. About half the patients (52.3%) believed they received a misdiagnosis at some point, either from a dermatologist, primary care clinician, or another type of physician. Patients first noticed DFSP at a median age of 29.6 years. Many of their lesions appeared initially as flat plaques that eventually became protuberant. Because of this disconnect between the disease name and its clinical presentation, the investigators proposed the alternative term, dermatofibrosarcoma, often protuberant, be adopted. The investigators concluded that “FBSGs appear to be powerful tools to synergize effective and rapid research collaborations with large numbers of international patients with rare disease.” TSJ

Investigators conducted a survey study of 214 patients with dermatofibrosarcoma protuberans (DFSP) or their family members using in part existing Facebook patient support groups (FBSG) to recruit respondents. They found the approach provides a “powerful” tool to collect relevant disease information from large numbers of patients with rare diseases.

A team of medical practitioners and patients developed the multiple-choice survey, and after testing the survey twice, posted a survey announcement on FBSGs for DFSP. The survey was live for 3 weeks in 2015. The investigators rapidly collected disease statistics, including information on recurrence, metastasis, surgical outcomes, diagnostic delay, and more, suggesting that FBSGs are useful medical research tools.

One hundred ninety-nine respondents were patients and 15 were family members. The respondents reported a median of 4 years to receive a correct diagnosis after noticing a lesion, ranging from less than 1 year to 42 years. About half the patients (52.3%) believed they received a misdiagnosis at some point, either from a dermatologist, primary care clinician, or another type of physician. Patients first noticed DFSP at a median age of 29.6 years. Many of their lesions appeared initially as flat plaques that eventually became protuberant. Because of this disconnect between the disease name and its clinical presentation, the investigators proposed the alternative term, dermatofibrosarcoma, often protuberant, be adopted. The investigators concluded that “FBSGs appear to be powerful tools to synergize effective and rapid research collaborations with large numbers of international patients with rare disease.” TSJ

Pexidartinib, the newly approved agent to treat patients with tenosynovial giant cell tumor (TGCT), received a category 1 recommendation from the National Comprehensive Cancer Network (NCCN) in the recent update of its Clinical Practice Guidelines in Oncology, Soft Tissue Sarcoma (Version 4.2019). A category 1 recommendation is based on a high level of evidence with uniform consensus that the intervention is appropriate.

The NCCN based its recommendation on the randomized, placebo-controlled phase 3 ENLIVEN study (NCT02371369) published in The Lancet (Tap WD, Gelderblom H, Palmerini E, et al. Lancet. 2019;394:478-487). The placebo-controlled portion of the study showed that patients treated with pexidartinib achieved a significantly higher overall response than patients in the placebo arm, 39% compared to none, respectively. The investigators identified mixed or cholestatic hepatotoxicity to be a risk of systemic therapy with the agent. Nevertheless, the “robust tumour response,” they wrote, “with improved patient symptoms and functional outcomes” establish pexidartinib as a potential treatment for TGCT in cases not amenable to improvement with surgery.

Pexidartinib, the newly approved agent to treat patients with tenosynovial giant cell tumor (TGCT), received a category 1 recommendation from the National Comprehensive Cancer Network (NCCN) in the recent update of its Clinical Practice Guidelines in Oncology, Soft Tissue Sarcoma (Version 4.2019). A category 1 recommendation is based on a high level of evidence with uniform consensus that the intervention is appropriate.

The NCCN based its recommendation on the randomized, placebo-controlled phase 3 ENLIVEN study (NCT02371369) published in The Lancet (Tap WD, Gelderblom H, Palmerini E, et al. Lancet. 2019;394:478-487). The placebo-controlled portion of the study showed that patients treated with pexidartinib achieved a significantly higher overall response than patients in the placebo arm, 39% compared to none, respectively. The investigators identified mixed or cholestatic hepatotoxicity to be a risk of systemic therapy with the agent. Nevertheless, the “robust tumour response,” they wrote, “with improved patient symptoms and functional outcomes” establish pexidartinib as a potential treatment for TGCT in cases not amenable to improvement with surgery.

Pexidartinib, the newly approved agent to treat patients with tenosynovial giant cell tumor (TGCT), received a category 1 recommendation from the National Comprehensive Cancer Network (NCCN) in the recent update of its Clinical Practice Guidelines in Oncology, Soft Tissue Sarcoma (Version 4.2019). A category 1 recommendation is based on a high level of evidence with uniform consensus that the intervention is appropriate.

The NCCN based its recommendation on the randomized, placebo-controlled phase 3 ENLIVEN study (NCT02371369) published in The Lancet (Tap WD, Gelderblom H, Palmerini E, et al. Lancet. 2019;394:478-487). The placebo-controlled portion of the study showed that patients treated with pexidartinib achieved a significantly higher overall response than patients in the placebo arm, 39% compared to none, respectively. The investigators identified mixed or cholestatic hepatotoxicity to be a risk of systemic therapy with the agent. Nevertheless, the “robust tumour response,” they wrote, “with improved patient symptoms and functional outcomes” establish pexidartinib as a potential treatment for TGCT in cases not amenable to improvement with surgery.

Angiosarcomas are malignant tumors of the vascular endothelium and are typically idiopathic. These tumors comprise 2% of all soft tissue sarcomas and have an estimated incidence of 2 per million.^1,2 Known causes of angiosarcoma include genetic syndromes—such as von Hippel- Lindau, Chuvash polycythemia, Bannayan- Riley-Ruvalcaba, Cowden, and hamartomatous polyposis syndromes— chronic lymphedema, and exposure to radiation.³ Vinyl chloride, arsenicals, and thorotrast are known to increase the incidence of liver angiosarcoma.⁴

Malignant transformation of hemangioma is rare. We describe metastatic angiosarcoma in a patient with a large, longterm treatment-resistant subcutaneous hemangioma, illustrating such a possibility. We review similar cases and discuss the value of determining pathogenesis in such patients.

Case Presentation and Summary

A 55-year-old female with a long-standing childhood hemangioma of the left lower extremity was referred to Ochsner Medical Center for tissue diagnosis of new pulmonary nodules. Her medical history included a 7 pack-year smoking history; she had quit 3 years prior. Her family history included a sister who died from breast cancer. The patient initially had a progressive, intermittently bleeding tumor in the left foot at age 7. She was diagnosed with hemangioma in her twenties. At that point, her tumor began to involve the posterior calf and femur, causing deformity. She had multiple surgical resections but reportedly all pathology demonstrated benign hemangioma. She received radiation for pain, a routine treatment at the time, but developed a focus of progression in the heel. Above-knee amputation was considered but could not be performed when hemangioma was discovered in the hip area. She was lost to follow-up between 2001 and 2015. Lower extremity magnetic resonance imaging in 2015 was stable with imaging prior to 2001. A repeat biopsy in 2016 demonstrated hemangioma. The patient then received radiation to a wider field, including the femur, with minimal response. She completed a course of steroids as well. Bevacizumab was started in 2017 and improved foot deformity. She also briefly trialed pazopanib for 4 weeks in 2018 in an attempt to switch to oral medications. Despite partial response, she discontinued both agents in July 2018 because of toxicity and the burden of recurrent infusions.

Four months later, she presented with 2 months of intermittent hemoptysis and 18 months of metallic odors. Additionally, she lost 25 pounds in 3 months, which she attributed to a diet plan. At this visit, her left lower extremity exhibited multiple subcutaneous tumors and nodules.

Computed tomography (CT) with contrast demonstrated innumerable pulmonary nodules, the largest measuring 2.2 cm in the right lower lobe superior segment. Positron emission tomography (PET)/CT revealed 2 nodules with mild hypermetabolic activity; the largest nodule had a maximum standardized uptake value of 2.7. Bronchoalveolar lavage studies showed intra-alveolar hemorrhage with hemosiderin-laden macrophages. No malignancy, granuloma, or dysplasia was found in transbronchial needle aspirate of the largest nodule. The patient had no lymphadenopathy.

At this hospital, surgical resection by video-assisted thoracoscopic surgery confirmed multifocal malignant epithelioid neoplasm suspicious for angiosarcoma. Multiple areas showed proliferation of atypical epithelioid-to-spindle cells. There were prominent associated hemosiderin-laden macrophages, fresh red blood cells, and dilated blood-filled spaces. Cells demonstrated hyperchromasia with irregular nuclear contours, prominent nucleoli, and mitoses  (FIGURE 1). Additionally, there were areas of focal organizing pneumonia. For atypical cells, staining was CD31-positive and CD34-negative. Staining was strongly positive for ERG. There was increased Ki-67 with retained INI expression and patchy weak reactivity for Fli-1.

Next-generation sequencing was performed. Specimen tumor content was 15%. Genomic findings included IDH1 p.R132C mutation, with variant allele frequency <10%. Testing was inconclusive for MSI and TMB mutations. PD-L1 assessment could not be performed. Unfortunately, the patient did not qualify for any clinical trials, as there were no matching alterations. This patient was lost to follow-up.

Discussion

Angiosarcoma accounts for 2% of soft tissue sarcomas.¹ Cutaneous angiosarcomas most commonly occur in the face and scalp of the elderly, or in sites of chronic lymphedema. Angiosarcoma also develops following radiation therapy.⁵ For breast cancers and tumors of the head and neck, irradiation has <1% risk of inducing secondary malignancy, including angiosarcoma.⁶

This patient had a new diagnosis of angiosarcoma in the setting of long-standing benign hemangioma with history of radiation treatment. Thus, it is unclear whether this angiosarcoma was primary, radiation-induced, or secondary to transformation from the preexisting vascular tumor. Post-irradiation sarcoma carries a less favorable prognosis compared to de novo sarcoma; however, reports conflict on whether this holds for angiosarcoma subtypes.⁶ Determining etiology may benefit patients for prognostication and possibly inform future selection of treatment modalities.

The mutational signature in radiation- associated sarcomas differs from that of sporadic sarcomas. First, radiation- associated sarcomas demonstrate more frequent small deletions and balanced translocations. TP53 mutations are found in up to 1/3 of radiation-associated sarcomas and are more often due to small deletions than in sporadic sarcomas.⁷ High-level MYC amplification occurs in 54%-100% of secondary angiosarcomas, compared to 0-7% in sporadic angiosarcomas. Co-amplification of FLT4 occurs in 11%-25% of secondary angiosarcomas.⁸ Additionally, transcriptome analysis revealed differential expression of a 135-gene signature compared to non-radiation- induced sarcomas.⁷ Although this patient was not specifically analyzed for such alterations, such tests may differentiate post-irradiation angiosarcoma from sporadic etiologies.

In this patient, the R132C IDH1 mutation was identified and may be the first reported case in angiosarcoma. Typically, this mutation occurs in chondrosarcoma, myeloid neoplasms, gliomas, and cholangiocarcinomas. It is also found in spindle cell hemangiomas but not in other vascular tumors.⁹ The clinical significance of this mutation is uncertain at this time.

There are approximately 36 reported cases of malignant disease arising in patients with less aggressive vascular tumors (TABLE 1). Of these, 25 of 36 involve angiosarcoma arising in patients with hemangioma. Four cases of angiosarcoma were reported in patients with hemangioendothelioma, 1 case of hemangioendothelioma in a patient with hemangioma, 1 case of Dabska tumor in a patient with hemangioma, and 1 case of angiosarcoma in a patient with Dabska tumor. Fifteen cases involved initial disease with adult onset and 21 involved initial disease with pediatric onset, suggesting even distribution. Malignant disease mostly occurred in adulthood, in 26 out of 33 cases. Latency to malignancy ranged from concurrent discovery to 54 years. Mean latency, excluding cases with concurrent discovery, was shorter with adult-onset initial disease, at 4.2 years, compared to 16 years among patients with onset of initial disease in childhood. Longer latency in the pediatric-onset population correlated with longer latent periods for radiation-induced angiosarcoma following benign disease, which is reported to average 23 years.¹⁰ Thirteen of 19 cases with pediatric onset disease had a history of radiotherapy, while 2 of 13 cases with adult onset disease did. Sixteen cases involved tumor in the bone and soft tissue, as in this patient. Notably, 4 of these cases involved long-standing hemangioma for 10 years or more, as in this patient, suggesting a possible correlation between long-standing vascular tumors and malignant transformation. Angiosarcoma arising in non-irradiated patients suggests that malignant transformation and de novo transformation may compete with radiation-induced mutation in tumorigenesis. Further, 8 cases involved angiosarcoma growing within another vascular tumor, demonstrating the possibility of malignant transformation. Dehner and Ishak described a histological model for quantifying such a risk; a validated model may be particularly useful in patients with long-standing hemangioma.¹¹

Etiology of tumorigenesis in cases of angiosarcoma arising in patients with a history of benign hemangioma may benefit prognostication and inform treatment selection in the future. Owing to long latent periods, radiation-associated angiosarcoma incidence may rise, as radiation therapy for benign hemangioma was recently routine. Future research may provide insight into disease progression and possibly predict the risk of angiosarcoma in patients with long-standing benign disease. TSJ

Angiosarcomas are malignant tumors of the vascular endothelium and are typically idiopathic. These tumors comprise 2% of all soft tissue sarcomas and have an estimated incidence of 2 per million.^1,2 Known causes of angiosarcoma include genetic syndromes—such as von Hippel- Lindau, Chuvash polycythemia, Bannayan- Riley-Ruvalcaba, Cowden, and hamartomatous polyposis syndromes— chronic lymphedema, and exposure to radiation.³ Vinyl chloride, arsenicals, and thorotrast are known to increase the incidence of liver angiosarcoma.⁴

Malignant transformation of hemangioma is rare. We describe metastatic angiosarcoma in a patient with a large, longterm treatment-resistant subcutaneous hemangioma, illustrating such a possibility. We review similar cases and discuss the value of determining pathogenesis in such patients.

Case Presentation and Summary

A 55-year-old female with a long-standing childhood hemangioma of the left lower extremity was referred to Ochsner Medical Center for tissue diagnosis of new pulmonary nodules. Her medical history included a 7 pack-year smoking history; she had quit 3 years prior. Her family history included a sister who died from breast cancer. The patient initially had a progressive, intermittently bleeding tumor in the left foot at age 7. She was diagnosed with hemangioma in her twenties. At that point, her tumor began to involve the posterior calf and femur, causing deformity. She had multiple surgical resections but reportedly all pathology demonstrated benign hemangioma. She received radiation for pain, a routine treatment at the time, but developed a focus of progression in the heel. Above-knee amputation was considered but could not be performed when hemangioma was discovered in the hip area. She was lost to follow-up between 2001 and 2015. Lower extremity magnetic resonance imaging in 2015 was stable with imaging prior to 2001. A repeat biopsy in 2016 demonstrated hemangioma. The patient then received radiation to a wider field, including the femur, with minimal response. She completed a course of steroids as well. Bevacizumab was started in 2017 and improved foot deformity. She also briefly trialed pazopanib for 4 weeks in 2018 in an attempt to switch to oral medications. Despite partial response, she discontinued both agents in July 2018 because of toxicity and the burden of recurrent infusions.

Four months later, she presented with 2 months of intermittent hemoptysis and 18 months of metallic odors. Additionally, she lost 25 pounds in 3 months, which she attributed to a diet plan. At this visit, her left lower extremity exhibited multiple subcutaneous tumors and nodules.

Computed tomography (CT) with contrast demonstrated innumerable pulmonary nodules, the largest measuring 2.2 cm in the right lower lobe superior segment. Positron emission tomography (PET)/CT revealed 2 nodules with mild hypermetabolic activity; the largest nodule had a maximum standardized uptake value of 2.7. Bronchoalveolar lavage studies showed intra-alveolar hemorrhage with hemosiderin-laden macrophages. No malignancy, granuloma, or dysplasia was found in transbronchial needle aspirate of the largest nodule. The patient had no lymphadenopathy.

At this hospital, surgical resection by video-assisted thoracoscopic surgery confirmed multifocal malignant epithelioid neoplasm suspicious for angiosarcoma. Multiple areas showed proliferation of atypical epithelioid-to-spindle cells. There were prominent associated hemosiderin-laden macrophages, fresh red blood cells, and dilated blood-filled spaces. Cells demonstrated hyperchromasia with irregular nuclear contours, prominent nucleoli, and mitoses  (FIGURE 1). Additionally, there were areas of focal organizing pneumonia. For atypical cells, staining was CD31-positive and CD34-negative. Staining was strongly positive for ERG. There was increased Ki-67 with retained INI expression and patchy weak reactivity for Fli-1.

Next-generation sequencing was performed. Specimen tumor content was 15%. Genomic findings included IDH1 p.R132C mutation, with variant allele frequency <10%. Testing was inconclusive for MSI and TMB mutations. PD-L1 assessment could not be performed. Unfortunately, the patient did not qualify for any clinical trials, as there were no matching alterations. This patient was lost to follow-up.

Discussion

Angiosarcoma accounts for 2% of soft tissue sarcomas.¹ Cutaneous angiosarcomas most commonly occur in the face and scalp of the elderly, or in sites of chronic lymphedema. Angiosarcoma also develops following radiation therapy.⁵ For breast cancers and tumors of the head and neck, irradiation has <1% risk of inducing secondary malignancy, including angiosarcoma.⁶

This patient had a new diagnosis of angiosarcoma in the setting of long-standing benign hemangioma with history of radiation treatment. Thus, it is unclear whether this angiosarcoma was primary, radiation-induced, or secondary to transformation from the preexisting vascular tumor. Post-irradiation sarcoma carries a less favorable prognosis compared to de novo sarcoma; however, reports conflict on whether this holds for angiosarcoma subtypes.⁶ Determining etiology may benefit patients for prognostication and possibly inform future selection of treatment modalities.

The mutational signature in radiation- associated sarcomas differs from that of sporadic sarcomas. First, radiation- associated sarcomas demonstrate more frequent small deletions and balanced translocations. TP53 mutations are found in up to 1/3 of radiation-associated sarcomas and are more often due to small deletions than in sporadic sarcomas.⁷ High-level MYC amplification occurs in 54%-100% of secondary angiosarcomas, compared to 0-7% in sporadic angiosarcomas. Co-amplification of FLT4 occurs in 11%-25% of secondary angiosarcomas.⁸ Additionally, transcriptome analysis revealed differential expression of a 135-gene signature compared to non-radiation- induced sarcomas.⁷ Although this patient was not specifically analyzed for such alterations, such tests may differentiate post-irradiation angiosarcoma from sporadic etiologies.

In this patient, the R132C IDH1 mutation was identified and may be the first reported case in angiosarcoma. Typically, this mutation occurs in chondrosarcoma, myeloid neoplasms, gliomas, and cholangiocarcinomas. It is also found in spindle cell hemangiomas but not in other vascular tumors.⁹ The clinical significance of this mutation is uncertain at this time.

There are approximately 36 reported cases of malignant disease arising in patients with less aggressive vascular tumors (TABLE 1). Of these, 25 of 36 involve angiosarcoma arising in patients with hemangioma. Four cases of angiosarcoma were reported in patients with hemangioendothelioma, 1 case of hemangioendothelioma in a patient with hemangioma, 1 case of Dabska tumor in a patient with hemangioma, and 1 case of angiosarcoma in a patient with Dabska tumor. Fifteen cases involved initial disease with adult onset and 21 involved initial disease with pediatric onset, suggesting even distribution. Malignant disease mostly occurred in adulthood, in 26 out of 33 cases. Latency to malignancy ranged from concurrent discovery to 54 years. Mean latency, excluding cases with concurrent discovery, was shorter with adult-onset initial disease, at 4.2 years, compared to 16 years among patients with onset of initial disease in childhood. Longer latency in the pediatric-onset population correlated with longer latent periods for radiation-induced angiosarcoma following benign disease, which is reported to average 23 years.¹⁰ Thirteen of 19 cases with pediatric onset disease had a history of radiotherapy, while 2 of 13 cases with adult onset disease did. Sixteen cases involved tumor in the bone and soft tissue, as in this patient. Notably, 4 of these cases involved long-standing hemangioma for 10 years or more, as in this patient, suggesting a possible correlation between long-standing vascular tumors and malignant transformation. Angiosarcoma arising in non-irradiated patients suggests that malignant transformation and de novo transformation may compete with radiation-induced mutation in tumorigenesis. Further, 8 cases involved angiosarcoma growing within another vascular tumor, demonstrating the possibility of malignant transformation. Dehner and Ishak described a histological model for quantifying such a risk; a validated model may be particularly useful in patients with long-standing hemangioma.¹¹

Etiology of tumorigenesis in cases of angiosarcoma arising in patients with a history of benign hemangioma may benefit prognostication and inform treatment selection in the future. Owing to long latent periods, radiation-associated angiosarcoma incidence may rise, as radiation therapy for benign hemangioma was recently routine. Future research may provide insight into disease progression and possibly predict the risk of angiosarcoma in patients with long-standing benign disease. TSJ

Angiosarcomas are malignant tumors of the vascular endothelium and are typically idiopathic. These tumors comprise 2% of all soft tissue sarcomas and have an estimated incidence of 2 per million.^1,2 Known causes of angiosarcoma include genetic syndromes—such as von Hippel- Lindau, Chuvash polycythemia, Bannayan- Riley-Ruvalcaba, Cowden, and hamartomatous polyposis syndromes— chronic lymphedema, and exposure to radiation.³ Vinyl chloride, arsenicals, and thorotrast are known to increase the incidence of liver angiosarcoma.⁴

Malignant transformation of hemangioma is rare. We describe metastatic angiosarcoma in a patient with a large, longterm treatment-resistant subcutaneous hemangioma, illustrating such a possibility. We review similar cases and discuss the value of determining pathogenesis in such patients.

Case Presentation and Summary

A 55-year-old female with a long-standing childhood hemangioma of the left lower extremity was referred to Ochsner Medical Center for tissue diagnosis of new pulmonary nodules. Her medical history included a 7 pack-year smoking history; she had quit 3 years prior. Her family history included a sister who died from breast cancer. The patient initially had a progressive, intermittently bleeding tumor in the left foot at age 7. She was diagnosed with hemangioma in her twenties. At that point, her tumor began to involve the posterior calf and femur, causing deformity. She had multiple surgical resections but reportedly all pathology demonstrated benign hemangioma. She received radiation for pain, a routine treatment at the time, but developed a focus of progression in the heel. Above-knee amputation was considered but could not be performed when hemangioma was discovered in the hip area. She was lost to follow-up between 2001 and 2015. Lower extremity magnetic resonance imaging in 2015 was stable with imaging prior to 2001. A repeat biopsy in 2016 demonstrated hemangioma. The patient then received radiation to a wider field, including the femur, with minimal response. She completed a course of steroids as well. Bevacizumab was started in 2017 and improved foot deformity. She also briefly trialed pazopanib for 4 weeks in 2018 in an attempt to switch to oral medications. Despite partial response, she discontinued both agents in July 2018 because of toxicity and the burden of recurrent infusions.

Four months later, she presented with 2 months of intermittent hemoptysis and 18 months of metallic odors. Additionally, she lost 25 pounds in 3 months, which she attributed to a diet plan. At this visit, her left lower extremity exhibited multiple subcutaneous tumors and nodules.

Computed tomography (CT) with contrast demonstrated innumerable pulmonary nodules, the largest measuring 2.2 cm in the right lower lobe superior segment. Positron emission tomography (PET)/CT revealed 2 nodules with mild hypermetabolic activity; the largest nodule had a maximum standardized uptake value of 2.7. Bronchoalveolar lavage studies showed intra-alveolar hemorrhage with hemosiderin-laden macrophages. No malignancy, granuloma, or dysplasia was found in transbronchial needle aspirate of the largest nodule. The patient had no lymphadenopathy.

At this hospital, surgical resection by video-assisted thoracoscopic surgery confirmed multifocal malignant epithelioid neoplasm suspicious for angiosarcoma. Multiple areas showed proliferation of atypical epithelioid-to-spindle cells. There were prominent associated hemosiderin-laden macrophages, fresh red blood cells, and dilated blood-filled spaces. Cells demonstrated hyperchromasia with irregular nuclear contours, prominent nucleoli, and mitoses  (FIGURE 1). Additionally, there were areas of focal organizing pneumonia. For atypical cells, staining was CD31-positive and CD34-negative. Staining was strongly positive for ERG. There was increased Ki-67 with retained INI expression and patchy weak reactivity for Fli-1.

Next-generation sequencing was performed. Specimen tumor content was 15%. Genomic findings included IDH1 p.R132C mutation, with variant allele frequency <10%. Testing was inconclusive for MSI and TMB mutations. PD-L1 assessment could not be performed. Unfortunately, the patient did not qualify for any clinical trials, as there were no matching alterations. This patient was lost to follow-up.

Discussion

Angiosarcoma accounts for 2% of soft tissue sarcomas.¹ Cutaneous angiosarcomas most commonly occur in the face and scalp of the elderly, or in sites of chronic lymphedema. Angiosarcoma also develops following radiation therapy.⁵ For breast cancers and tumors of the head and neck, irradiation has <1% risk of inducing secondary malignancy, including angiosarcoma.⁶

This patient had a new diagnosis of angiosarcoma in the setting of long-standing benign hemangioma with history of radiation treatment. Thus, it is unclear whether this angiosarcoma was primary, radiation-induced, or secondary to transformation from the preexisting vascular tumor. Post-irradiation sarcoma carries a less favorable prognosis compared to de novo sarcoma; however, reports conflict on whether this holds for angiosarcoma subtypes.⁶ Determining etiology may benefit patients for prognostication and possibly inform future selection of treatment modalities.

The mutational signature in radiation- associated sarcomas differs from that of sporadic sarcomas. First, radiation- associated sarcomas demonstrate more frequent small deletions and balanced translocations. TP53 mutations are found in up to 1/3 of radiation-associated sarcomas and are more often due to small deletions than in sporadic sarcomas.⁷ High-level MYC amplification occurs in 54%-100% of secondary angiosarcomas, compared to 0-7% in sporadic angiosarcomas. Co-amplification of FLT4 occurs in 11%-25% of secondary angiosarcomas.⁸ Additionally, transcriptome analysis revealed differential expression of a 135-gene signature compared to non-radiation- induced sarcomas.⁷ Although this patient was not specifically analyzed for such alterations, such tests may differentiate post-irradiation angiosarcoma from sporadic etiologies.

In this patient, the R132C IDH1 mutation was identified and may be the first reported case in angiosarcoma. Typically, this mutation occurs in chondrosarcoma, myeloid neoplasms, gliomas, and cholangiocarcinomas. It is also found in spindle cell hemangiomas but not in other vascular tumors.⁹ The clinical significance of this mutation is uncertain at this time.

There are approximately 36 reported cases of malignant disease arising in patients with less aggressive vascular tumors (TABLE 1). Of these, 25 of 36 involve angiosarcoma arising in patients with hemangioma. Four cases of angiosarcoma were reported in patients with hemangioendothelioma, 1 case of hemangioendothelioma in a patient with hemangioma, 1 case of Dabska tumor in a patient with hemangioma, and 1 case of angiosarcoma in a patient with Dabska tumor. Fifteen cases involved initial disease with adult onset and 21 involved initial disease with pediatric onset, suggesting even distribution. Malignant disease mostly occurred in adulthood, in 26 out of 33 cases. Latency to malignancy ranged from concurrent discovery to 54 years. Mean latency, excluding cases with concurrent discovery, was shorter with adult-onset initial disease, at 4.2 years, compared to 16 years among patients with onset of initial disease in childhood. Longer latency in the pediatric-onset population correlated with longer latent periods for radiation-induced angiosarcoma following benign disease, which is reported to average 23 years.¹⁰ Thirteen of 19 cases with pediatric onset disease had a history of radiotherapy, while 2 of 13 cases with adult onset disease did. Sixteen cases involved tumor in the bone and soft tissue, as in this patient. Notably, 4 of these cases involved long-standing hemangioma for 10 years or more, as in this patient, suggesting a possible correlation between long-standing vascular tumors and malignant transformation. Angiosarcoma arising in non-irradiated patients suggests that malignant transformation and de novo transformation may compete with radiation-induced mutation in tumorigenesis. Further, 8 cases involved angiosarcoma growing within another vascular tumor, demonstrating the possibility of malignant transformation. Dehner and Ishak described a histological model for quantifying such a risk; a validated model may be particularly useful in patients with long-standing hemangioma.¹¹

Etiology of tumorigenesis in cases of angiosarcoma arising in patients with a history of benign hemangioma may benefit prognostication and inform treatment selection in the future. Owing to long latent periods, radiation-associated angiosarcoma incidence may rise, as radiation therapy for benign hemangioma was recently routine. Future research may provide insight into disease progression and possibly predict the risk of angiosarcoma in patients with long-standing benign disease. TSJ

You’ve probably heard of a “nocturnist,” but have you ever heard of a “weekendist?”

The field of hospital medicine (HM) has evolved dramatically since the term “hospitalist” was introduced in the literature in 1996.¹ There is a saying in HM that “if you know one HM program, you know one HM program,” alluding to the fact that every HM program is unique. The diversity of individual HM programs combined with the overall evolution of the field has expanded the range of jobs available in HM.

The nomenclature of adding an -ist to the end of the specific roles (e.g., nocturnist, weekendist) has become commonplace. These roles have developed with the increasing need for day and night staffing at many hospitals secondary to increased and more complex patients, less availability of residents because of work hour restrictions, and the Accreditation Council for Graduate Medical Education (ACGME) rules that require overnight supervision of residents

Additionally, the field of HM increasingly includes physicians trained in internal medicine, family medicine, pediatrics, and medicine-pediatrics (med-peds). In this article, we describe the variety of roles available to trainees joining HM and the multitude of different training backgrounds hospitalists come from.

Nocturnists

The 2018 State of Hospital Medicine Report notes that 76.1% of adult-only HM groups have nocturnists, hospitalists who work primarily at night to admit and to provide coverage for admitted patients.² Nocturnists often provide benefit to the rest of their hospitalist group by allowing fewer required night shifts for those that prefer to work during the day.

Nocturnists may choose a nighttime schedule for several reasons, including the ability to be home more during the day. They also have the potential to work fewer total hours or shifts while still earning a similar or increased income, compared with predominantly daytime hospitalists, increasing their flexibility to pursue other interests. These nocturnists become experts in navigating the admission process and responding to inpatient emergencies often with less support when compared with daytime hospitalists.

In addition to career nocturnist work, nocturnist jobs can be a great fit for those residency graduates who are undecided about fellowship and enjoy the acuity of inpatient medicine. It provides an opportunity to hone their clinical skill set prior to specialized training while earning an attending salary, and offers flexible hours which may allow for research or other endeavors. In academic centers, nocturnist educational roles take on a different character as well and may involve more 1:1 educational experiences. The role of nocturnists as educators is expanding as ACGME rules call for more oversight and educational opportunities for residents who are working at night.

However, challenges exist for nocturnists, including keeping abreast of new changes in their HM groups and hospital systems and engaging in quality initiatives, given that most meetings occur during the day. Additionally, nocturnists must adapt to sleeping during the day, potentially getting less sleep then they would otherwise and being “off cycle” with family and friends. For nocturnists raising children, being off cycle may be advantageous as it can allow them to be home with their children after school.

Weekendists

Another common hospitalist role is the weekendist, hospitalists who spend much of their clinical time preferentially working weekends. Similar to nocturnists, weekendists provide benefit to their hospitalist group by allowing others to have more weekends off.

Weekendists may prefer working weekends because of fewer total shifts or hours and/or higher compensation per shift. Additionally, weekendists have the flexibility to do other work on weekdays, such as research or another hospitalist job. For those that do nonclinical work during the week, a weekendist position may allow them to keep their clinical skills up to date. However, weekendists may face intense clinical days with a higher census because of fewer hospitalists rounding on the weekends.

Weekendists must balance having more potential time available during the weekdays but less time on the weekends to devote to family and friends. Furthermore, weekendists may feel less engaged with nonclinical opportunities, including quality improvement, educational offerings, and teaching opportunities.

SNFists

With increasing emphasis on transitions of care and the desire to avoid readmission penalties, some hospitalists have transitioned to work partly or primarily in skilled nursing facilities (SNF) and have been referred to as “SNFists.” Some of these hospitalists may split their clinical time between SNFs and acute care hospitals, while others may work exclusively at SNFs.

SNFists have the potential to be invaluable in improving transitions of care after discharge to post–acute care facilities because of increased provider presence in these facilities, comfort with medically complex patients, and appreciation of government regulations.⁴ SNFists may face potential challenges of needing to staff more than one post–acute care hospital and of having less resources available, compared with an acute care hospital.

Specific specialty hospitalists

For a variety of reasons including clinical interest, many hospitalists have become specialized with regards to their primary inpatient population. Some hospitalists spend the majority of their clinical time on a specific service in the hospital, often working closely with the subspecialist caring for that patient. These hospitalists may focus on hematology, oncology, bone-marrow transplant, neurology, cardiology, surgery services, or critical care, among others. Hospitalists focused on a specific service often become knowledge experts in that specialty. Conversely, by focusing on a specific service, certain pathologies may be less commonly seen, which may narrow the breadth of the hospital medicine job.

Hospitalist training

Internal medicine hospitalists may be the most common hospitalists encountered in many hospitals and at each Society of Hospital Medicine annual conference, but there has also been rapid growth in hospitalists from other specialties and backgrounds.

Family medicine hospitalists are a part of 64.9% of HM groups and about 9% of family medicine graduates are choosing HM as a career path.^2,3 Most family medicine hospitalists work in adult HM groups, but some, particularly in rural or academic settings, care for pediatric, newborn, and/or maternity patients. Similarly, pediatric hospitalists have become entrenched at many hospitals where children are admitted. These pediatric hospitalists, like adult hospitalists, may work in a variety of different clinical roles including in EDs, newborn nurseries, and inpatient wards or ICUs; they may also provide consult, sedation, or procedural services.

Med-peds hospitalists that split time between internal medicine and pediatrics are becoming more commonplace in the field. Many work at academic centers where they often work on each side separately, doing the same work as their internal medicine or pediatrics colleagues, and then switching to the other side after a period of time. Some centers offer unique roles for med-peds hospitalists including working on adult consult teams in children’s hospitals, where they provide consult care to older patients that may still receive their care at a children’s hospital. There are also nonacademic hospitals that primarily staff med-peds hospitalists, where they can provide the full spectrum of care from the newborn nursery to the inpatient pediatric and adult wards.

Hospital medicine is a young field that is constantly changing with new and developing roles for hospitalists from a wide variety of backgrounds. Stick around to see which “-ist” will come next in HM.

Dr. Hall is a med-peds hospitalist and assistant professor at the University of Kentucky, Lexington. Dr. Sanyal-Dey is an academic hospitalist at Zuckerberg San Francisco General Hospital and Trauma Center and the University of California, San Francisco, where she is the director of clinical operations, and director of the faculty inpatient service. Dr. Chang is associate professor and interprofessional education thread director (MD curriculum) at Washington University, St. Louis. Dr. Kwan is a hospitalist at the Veterans Affairs San Diego Healthcare System and associate professor at the University of California, San Diego. He is the chair of SHM’s Physicians in Training committee. Dr. Seymour is family medicine hospitalist education director at the University of Massachusetts Memorial Medical Center, Worcester, and associate professor at the University of Massachusetts.

References

1. Wachter RM, Goldman L. The Emerging Role of “Hospitalists” in the American Health Care System. N Engl J Med. 1996;335(7):514-7.

2. 2018 State of Hospital Medicine Report. Philadelphia: Society of Hospital Medicine, 2018.

3. Weaver SP, Hill J. Academician Attitudes and Beliefs Regarding the Use of Hospitalists: A CERA Study. Fam Med. 2015;47(5):357-61.

4. Teno JM et al. Temporal Trends in the Numbers of Skilled Nursing Facility Specialists From 2007 Through 2014. JAMA Intern Med. 2017;177(9):1376-8.

You’ve probably heard of a “nocturnist,” but have you ever heard of a “weekendist?”

The field of hospital medicine (HM) has evolved dramatically since the term “hospitalist” was introduced in the literature in 1996.¹ There is a saying in HM that “if you know one HM program, you know one HM program,” alluding to the fact that every HM program is unique. The diversity of individual HM programs combined with the overall evolution of the field has expanded the range of jobs available in HM.

The nomenclature of adding an -ist to the end of the specific roles (e.g., nocturnist, weekendist) has become commonplace. These roles have developed with the increasing need for day and night staffing at many hospitals secondary to increased and more complex patients, less availability of residents because of work hour restrictions, and the Accreditation Council for Graduate Medical Education (ACGME) rules that require overnight supervision of residents

Additionally, the field of HM increasingly includes physicians trained in internal medicine, family medicine, pediatrics, and medicine-pediatrics (med-peds). In this article, we describe the variety of roles available to trainees joining HM and the multitude of different training backgrounds hospitalists come from.

Nocturnists

The 2018 State of Hospital Medicine Report notes that 76.1% of adult-only HM groups have nocturnists, hospitalists who work primarily at night to admit and to provide coverage for admitted patients.² Nocturnists often provide benefit to the rest of their hospitalist group by allowing fewer required night shifts for those that prefer to work during the day.

Nocturnists may choose a nighttime schedule for several reasons, including the ability to be home more during the day. They also have the potential to work fewer total hours or shifts while still earning a similar or increased income, compared with predominantly daytime hospitalists, increasing their flexibility to pursue other interests. These nocturnists become experts in navigating the admission process and responding to inpatient emergencies often with less support when compared with daytime hospitalists.

In addition to career nocturnist work, nocturnist jobs can be a great fit for those residency graduates who are undecided about fellowship and enjoy the acuity of inpatient medicine. It provides an opportunity to hone their clinical skill set prior to specialized training while earning an attending salary, and offers flexible hours which may allow for research or other endeavors. In academic centers, nocturnist educational roles take on a different character as well and may involve more 1:1 educational experiences. The role of nocturnists as educators is expanding as ACGME rules call for more oversight and educational opportunities for residents who are working at night.

However, challenges exist for nocturnists, including keeping abreast of new changes in their HM groups and hospital systems and engaging in quality initiatives, given that most meetings occur during the day. Additionally, nocturnists must adapt to sleeping during the day, potentially getting less sleep then they would otherwise and being “off cycle” with family and friends. For nocturnists raising children, being off cycle may be advantageous as it can allow them to be home with their children after school.

Weekendists

Another common hospitalist role is the weekendist, hospitalists who spend much of their clinical time preferentially working weekends. Similar to nocturnists, weekendists provide benefit to their hospitalist group by allowing others to have more weekends off.

Weekendists may prefer working weekends because of fewer total shifts or hours and/or higher compensation per shift. Additionally, weekendists have the flexibility to do other work on weekdays, such as research or another hospitalist job. For those that do nonclinical work during the week, a weekendist position may allow them to keep their clinical skills up to date. However, weekendists may face intense clinical days with a higher census because of fewer hospitalists rounding on the weekends.

Weekendists must balance having more potential time available during the weekdays but less time on the weekends to devote to family and friends. Furthermore, weekendists may feel less engaged with nonclinical opportunities, including quality improvement, educational offerings, and teaching opportunities.

SNFists

With increasing emphasis on transitions of care and the desire to avoid readmission penalties, some hospitalists have transitioned to work partly or primarily in skilled nursing facilities (SNF) and have been referred to as “SNFists.” Some of these hospitalists may split their clinical time between SNFs and acute care hospitals, while others may work exclusively at SNFs.

SNFists have the potential to be invaluable in improving transitions of care after discharge to post–acute care facilities because of increased provider presence in these facilities, comfort with medically complex patients, and appreciation of government regulations.⁴ SNFists may face potential challenges of needing to staff more than one post–acute care hospital and of having less resources available, compared with an acute care hospital.

Specific specialty hospitalists

For a variety of reasons including clinical interest, many hospitalists have become specialized with regards to their primary inpatient population. Some hospitalists spend the majority of their clinical time on a specific service in the hospital, often working closely with the subspecialist caring for that patient. These hospitalists may focus on hematology, oncology, bone-marrow transplant, neurology, cardiology, surgery services, or critical care, among others. Hospitalists focused on a specific service often become knowledge experts in that specialty. Conversely, by focusing on a specific service, certain pathologies may be less commonly seen, which may narrow the breadth of the hospital medicine job.

Hospitalist training

Internal medicine hospitalists may be the most common hospitalists encountered in many hospitals and at each Society of Hospital Medicine annual conference, but there has also been rapid growth in hospitalists from other specialties and backgrounds.

Family medicine hospitalists are a part of 64.9% of HM groups and about 9% of family medicine graduates are choosing HM as a career path.^2,3 Most family medicine hospitalists work in adult HM groups, but some, particularly in rural or academic settings, care for pediatric, newborn, and/or maternity patients. Similarly, pediatric hospitalists have become entrenched at many hospitals where children are admitted. These pediatric hospitalists, like adult hospitalists, may work in a variety of different clinical roles including in EDs, newborn nurseries, and inpatient wards or ICUs; they may also provide consult, sedation, or procedural services.

Med-peds hospitalists that split time between internal medicine and pediatrics are becoming more commonplace in the field. Many work at academic centers where they often work on each side separately, doing the same work as their internal medicine or pediatrics colleagues, and then switching to the other side after a period of time. Some centers offer unique roles for med-peds hospitalists including working on adult consult teams in children’s hospitals, where they provide consult care to older patients that may still receive their care at a children’s hospital. There are also nonacademic hospitals that primarily staff med-peds hospitalists, where they can provide the full spectrum of care from the newborn nursery to the inpatient pediatric and adult wards.

Hospital medicine is a young field that is constantly changing with new and developing roles for hospitalists from a wide variety of backgrounds. Stick around to see which “-ist” will come next in HM.

Dr. Hall is a med-peds hospitalist and assistant professor at the University of Kentucky, Lexington. Dr. Sanyal-Dey is an academic hospitalist at Zuckerberg San Francisco General Hospital and Trauma Center and the University of California, San Francisco, where she is the director of clinical operations, and director of the faculty inpatient service. Dr. Chang is associate professor and interprofessional education thread director (MD curriculum) at Washington University, St. Louis. Dr. Kwan is a hospitalist at the Veterans Affairs San Diego Healthcare System and associate professor at the University of California, San Diego. He is the chair of SHM’s Physicians in Training committee. Dr. Seymour is family medicine hospitalist education director at the University of Massachusetts Memorial Medical Center, Worcester, and associate professor at the University of Massachusetts.

References

1. Wachter RM, Goldman L. The Emerging Role of “Hospitalists” in the American Health Care System. N Engl J Med. 1996;335(7):514-7.

2. 2018 State of Hospital Medicine Report. Philadelphia: Society of Hospital Medicine, 2018.

3. Weaver SP, Hill J. Academician Attitudes and Beliefs Regarding the Use of Hospitalists: A CERA Study. Fam Med. 2015;47(5):357-61.

4. Teno JM et al. Temporal Trends in the Numbers of Skilled Nursing Facility Specialists From 2007 Through 2014. JAMA Intern Med. 2017;177(9):1376-8.

You’ve probably heard of a “nocturnist,” but have you ever heard of a “weekendist?”

The field of hospital medicine (HM) has evolved dramatically since the term “hospitalist” was introduced in the literature in 1996.¹ There is a saying in HM that “if you know one HM program, you know one HM program,” alluding to the fact that every HM program is unique. The diversity of individual HM programs combined with the overall evolution of the field has expanded the range of jobs available in HM.

The nomenclature of adding an -ist to the end of the specific roles (e.g., nocturnist, weekendist) has become commonplace. These roles have developed with the increasing need for day and night staffing at many hospitals secondary to increased and more complex patients, less availability of residents because of work hour restrictions, and the Accreditation Council for Graduate Medical Education (ACGME) rules that require overnight supervision of residents

Additionally, the field of HM increasingly includes physicians trained in internal medicine, family medicine, pediatrics, and medicine-pediatrics (med-peds). In this article, we describe the variety of roles available to trainees joining HM and the multitude of different training backgrounds hospitalists come from.

Nocturnists

The 2018 State of Hospital Medicine Report notes that 76.1% of adult-only HM groups have nocturnists, hospitalists who work primarily at night to admit and to provide coverage for admitted patients.² Nocturnists often provide benefit to the rest of their hospitalist group by allowing fewer required night shifts for those that prefer to work during the day.

Nocturnists may choose a nighttime schedule for several reasons, including the ability to be home more during the day. They also have the potential to work fewer total hours or shifts while still earning a similar or increased income, compared with predominantly daytime hospitalists, increasing their flexibility to pursue other interests. These nocturnists become experts in navigating the admission process and responding to inpatient emergencies often with less support when compared with daytime hospitalists.

In addition to career nocturnist work, nocturnist jobs can be a great fit for those residency graduates who are undecided about fellowship and enjoy the acuity of inpatient medicine. It provides an opportunity to hone their clinical skill set prior to specialized training while earning an attending salary, and offers flexible hours which may allow for research or other endeavors. In academic centers, nocturnist educational roles take on a different character as well and may involve more 1:1 educational experiences. The role of nocturnists as educators is expanding as ACGME rules call for more oversight and educational opportunities for residents who are working at night.

However, challenges exist for nocturnists, including keeping abreast of new changes in their HM groups and hospital systems and engaging in quality initiatives, given that most meetings occur during the day. Additionally, nocturnists must adapt to sleeping during the day, potentially getting less sleep then they would otherwise and being “off cycle” with family and friends. For nocturnists raising children, being off cycle may be advantageous as it can allow them to be home with their children after school.

Weekendists

Another common hospitalist role is the weekendist, hospitalists who spend much of their clinical time preferentially working weekends. Similar to nocturnists, weekendists provide benefit to their hospitalist group by allowing others to have more weekends off.

Weekendists may prefer working weekends because of fewer total shifts or hours and/or higher compensation per shift. Additionally, weekendists have the flexibility to do other work on weekdays, such as research or another hospitalist job. For those that do nonclinical work during the week, a weekendist position may allow them to keep their clinical skills up to date. However, weekendists may face intense clinical days with a higher census because of fewer hospitalists rounding on the weekends.

Weekendists must balance having more potential time available during the weekdays but less time on the weekends to devote to family and friends. Furthermore, weekendists may feel less engaged with nonclinical opportunities, including quality improvement, educational offerings, and teaching opportunities.

SNFists

With increasing emphasis on transitions of care and the desire to avoid readmission penalties, some hospitalists have transitioned to work partly or primarily in skilled nursing facilities (SNF) and have been referred to as “SNFists.” Some of these hospitalists may split their clinical time between SNFs and acute care hospitals, while others may work exclusively at SNFs.

SNFists have the potential to be invaluable in improving transitions of care after discharge to post–acute care facilities because of increased provider presence in these facilities, comfort with medically complex patients, and appreciation of government regulations.⁴ SNFists may face potential challenges of needing to staff more than one post–acute care hospital and of having less resources available, compared with an acute care hospital.

Specific specialty hospitalists

For a variety of reasons including clinical interest, many hospitalists have become specialized with regards to their primary inpatient population. Some hospitalists spend the majority of their clinical time on a specific service in the hospital, often working closely with the subspecialist caring for that patient. These hospitalists may focus on hematology, oncology, bone-marrow transplant, neurology, cardiology, surgery services, or critical care, among others. Hospitalists focused on a specific service often become knowledge experts in that specialty. Conversely, by focusing on a specific service, certain pathologies may be less commonly seen, which may narrow the breadth of the hospital medicine job.

Hospitalist training

Internal medicine hospitalists may be the most common hospitalists encountered in many hospitals and at each Society of Hospital Medicine annual conference, but there has also been rapid growth in hospitalists from other specialties and backgrounds.

Family medicine hospitalists are a part of 64.9% of HM groups and about 9% of family medicine graduates are choosing HM as a career path.^2,3 Most family medicine hospitalists work in adult HM groups, but some, particularly in rural or academic settings, care for pediatric, newborn, and/or maternity patients. Similarly, pediatric hospitalists have become entrenched at many hospitals where children are admitted. These pediatric hospitalists, like adult hospitalists, may work in a variety of different clinical roles including in EDs, newborn nurseries, and inpatient wards or ICUs; they may also provide consult, sedation, or procedural services.

Med-peds hospitalists that split time between internal medicine and pediatrics are becoming more commonplace in the field. Many work at academic centers where they often work on each side separately, doing the same work as their internal medicine or pediatrics colleagues, and then switching to the other side after a period of time. Some centers offer unique roles for med-peds hospitalists including working on adult consult teams in children’s hospitals, where they provide consult care to older patients that may still receive their care at a children’s hospital. There are also nonacademic hospitals that primarily staff med-peds hospitalists, where they can provide the full spectrum of care from the newborn nursery to the inpatient pediatric and adult wards.

Hospital medicine is a young field that is constantly changing with new and developing roles for hospitalists from a wide variety of backgrounds. Stick around to see which “-ist” will come next in HM.

Dr. Hall is a med-peds hospitalist and assistant professor at the University of Kentucky, Lexington. Dr. Sanyal-Dey is an academic hospitalist at Zuckerberg San Francisco General Hospital and Trauma Center and the University of California, San Francisco, where she is the director of clinical operations, and director of the faculty inpatient service. Dr. Chang is associate professor and interprofessional education thread director (MD curriculum) at Washington University, St. Louis. Dr. Kwan is a hospitalist at the Veterans Affairs San Diego Healthcare System and associate professor at the University of California, San Diego. He is the chair of SHM’s Physicians in Training committee. Dr. Seymour is family medicine hospitalist education director at the University of Massachusetts Memorial Medical Center, Worcester, and associate professor at the University of Massachusetts.

References

1. Wachter RM, Goldman L. The Emerging Role of “Hospitalists” in the American Health Care System. N Engl J Med. 1996;335(7):514-7.

2. 2018 State of Hospital Medicine Report. Philadelphia: Society of Hospital Medicine, 2018.

3. Weaver SP, Hill J. Academician Attitudes and Beliefs Regarding the Use of Hospitalists: A CERA Study. Fam Med. 2015;47(5):357-61.

4. Teno JM et al. Temporal Trends in the Numbers of Skilled Nursing Facility Specialists From 2007 Through 2014. JAMA Intern Med. 2017;177(9):1376-8.

SAN ANTONIO – For patients with early triple-negative breast cancer (TNBC), adding capecitabine to standard adjuvant chemotherapy may extend disease-free survival (DFS), based results of a phase 3 trial conducted in China.

Will Pass/MDedge News

Although capecitabine boosted DFS by approximately 6%, overall survival remained unchanged, reported lead author Junjie Li, MD, of Fudan University in Shanghai, China.

In a presentation at the San Antonio Breast Cancer Symposium, Dr. Li explained that these findings provide much-needed support for the concomitant use of capecitabine in breast cancer.

“Capecitabine has been proven [effective] in advanced breast cancer, while in earlier stage disease, available data are still inconsistent,” Dr. Li said.

To help resolve some of this uncertainty, Dr. Li and colleagues conducted an open-label, phase 3 trial involving 585 patients with TNBC who were either node positive or negative and had tumors more than 1 cm in diameter. Patients were randomized in a 1:1 ratio to receive either standard therapy with three cycles of docetaxel followed by three cycles of cyclophosphamide, epirubicin, and fluorouracil; or three cycles of capecitabine and docetaxel followed by three cycles of cyclophosphamide, epirubicin, and capecitabine.

After a median follow-up of 67 months, 288 patients had received the capecitabine regimen and 273 had undergone standard therapy. The 5-year DFS was significantly longer in the capecitabine group, at 86.26%, than the control group, at 80.23% (hazard ratio, 0.66; P = .038). This benefit extended across subgroups, Dr. Li noted. While a slight numerical difference in overall survival was seen between capecitabine and control arms, this was not statistically significant (93.27% vs. 90.55%).

The investigators described safety profiles between treatment arms as “generally comparable.” In the capecitabine group, more than one-third of patients (38.89%) had dose reductions, while 8.42% reported grade 3-4 hand-foot syndrome. Grade 3-4 toxicities were more common in the capecitabine group, including neutropenia (45.79% vs. 41.32%) and febrile neutropenia (16.5% vs. 15.97%).

“Capecitabine concomitant use with docetaxel and epirubicin may significantly improve disease-free survival in early triple-negative patients,” Dr. Li concluded. He suggested that the study regimen be viewed as an alternative adjuvant regimen, as it provided clinically meaningful improvements in survival while maintaining tolerability.

Conference attendee Mohamed El-Naghy, MD, PhD, a practicing oncologist in Oneida, N.Y., expressed concern for one aspect of the trial methodology during the question and answer session following Dr. Li’s presentation: Although all patients in the trial were considered triple negative, 10 patients had estrogen receptor/progesterone receptor (ER/PR) expression ranging from 1 to 9%, which conflicts with the definition of TNBCr provided by current guidelines, according to Dr. Li.

“It is always important to have common language,” Dr. El-Naghy said. “And if you define [TNBC by] ER/PR negativity, and still you have 10% [expression], that is unacceptable. The whole point is, I looked at your numbers – 10 patients in the whole study – maybe you say they are triple negative, but these [patients] are contamination to your sample.”

Responding to this comment, Dr. Li said that the data from these patients had a minimal impact on the study results.

“We did another analysis to exclude these 10 patients, but still the result is quite similar, because they are just 10 patients – 5 in each group,” Dr. Li said.

Will Pass/MDedge News

Invited discussant Priyanka Sharma, MD, of the University of Kansas Medical Center, Kansas City, offered some additional viewpoints on the trial.

“A large proportion of patients had non–grade III disease, and one could say that the dose of docetaxel monotherapy in the control arm was not the traditional 100 mg/m², and that could have negatively impacted the outcomes in the control arm,” Dr. Sharma said. “In addition, the trial is representative of patients only from China, and whether these findings would hold true in other ethnic and racial groups is not known. Furthermore, there seemed to be limited efficacy in patients with N0 disease, which comprised two-thirds of the trial.”

Despite these potential limitations, based on the trial results and other evidence, Dr. Sharma suggested that adding capecitabine to standard systemic therapy may be considered a viable option for patients with early TNBC.

The investigators reported no disclosures.

SOURCE: Li J et al. SABCS 2019, Abstract GS1-08.

SAN ANTONIO – For patients with early triple-negative breast cancer (TNBC), adding capecitabine to standard adjuvant chemotherapy may extend disease-free survival (DFS), based results of a phase 3 trial conducted in China.

Will Pass/MDedge News

Although capecitabine boosted DFS by approximately 6%, overall survival remained unchanged, reported lead author Junjie Li, MD, of Fudan University in Shanghai, China.

In a presentation at the San Antonio Breast Cancer Symposium, Dr. Li explained that these findings provide much-needed support for the concomitant use of capecitabine in breast cancer.

“Capecitabine has been proven [effective] in advanced breast cancer, while in earlier stage disease, available data are still inconsistent,” Dr. Li said.

To help resolve some of this uncertainty, Dr. Li and colleagues conducted an open-label, phase 3 trial involving 585 patients with TNBC who were either node positive or negative and had tumors more than 1 cm in diameter. Patients were randomized in a 1:1 ratio to receive either standard therapy with three cycles of docetaxel followed by three cycles of cyclophosphamide, epirubicin, and fluorouracil; or three cycles of capecitabine and docetaxel followed by three cycles of cyclophosphamide, epirubicin, and capecitabine.

After a median follow-up of 67 months, 288 patients had received the capecitabine regimen and 273 had undergone standard therapy. The 5-year DFS was significantly longer in the capecitabine group, at 86.26%, than the control group, at 80.23% (hazard ratio, 0.66; P = .038). This benefit extended across subgroups, Dr. Li noted. While a slight numerical difference in overall survival was seen between capecitabine and control arms, this was not statistically significant (93.27% vs. 90.55%).

The investigators described safety profiles between treatment arms as “generally comparable.” In the capecitabine group, more than one-third of patients (38.89%) had dose reductions, while 8.42% reported grade 3-4 hand-foot syndrome. Grade 3-4 toxicities were more common in the capecitabine group, including neutropenia (45.79% vs. 41.32%) and febrile neutropenia (16.5% vs. 15.97%).

“Capecitabine concomitant use with docetaxel and epirubicin may significantly improve disease-free survival in early triple-negative patients,” Dr. Li concluded. He suggested that the study regimen be viewed as an alternative adjuvant regimen, as it provided clinically meaningful improvements in survival while maintaining tolerability.

Conference attendee Mohamed El-Naghy, MD, PhD, a practicing oncologist in Oneida, N.Y., expressed concern for one aspect of the trial methodology during the question and answer session following Dr. Li’s presentation: Although all patients in the trial were considered triple negative, 10 patients had estrogen receptor/progesterone receptor (ER/PR) expression ranging from 1 to 9%, which conflicts with the definition of TNBCr provided by current guidelines, according to Dr. Li.

“It is always important to have common language,” Dr. El-Naghy said. “And if you define [TNBC by] ER/PR negativity, and still you have 10% [expression], that is unacceptable. The whole point is, I looked at your numbers – 10 patients in the whole study – maybe you say they are triple negative, but these [patients] are contamination to your sample.”

Responding to this comment, Dr. Li said that the data from these patients had a minimal impact on the study results.

“We did another analysis to exclude these 10 patients, but still the result is quite similar, because they are just 10 patients – 5 in each group,” Dr. Li said.

Will Pass/MDedge News

Invited discussant Priyanka Sharma, MD, of the University of Kansas Medical Center, Kansas City, offered some additional viewpoints on the trial.

“A large proportion of patients had non–grade III disease, and one could say that the dose of docetaxel monotherapy in the control arm was not the traditional 100 mg/m², and that could have negatively impacted the outcomes in the control arm,” Dr. Sharma said. “In addition, the trial is representative of patients only from China, and whether these findings would hold true in other ethnic and racial groups is not known. Furthermore, there seemed to be limited efficacy in patients with N0 disease, which comprised two-thirds of the trial.”

Despite these potential limitations, based on the trial results and other evidence, Dr. Sharma suggested that adding capecitabine to standard systemic therapy may be considered a viable option for patients with early TNBC.

The investigators reported no disclosures.

SOURCE: Li J et al. SABCS 2019, Abstract GS1-08.

SAN ANTONIO – For patients with early triple-negative breast cancer (TNBC), adding capecitabine to standard adjuvant chemotherapy may extend disease-free survival (DFS), based results of a phase 3 trial conducted in China.

Will Pass/MDedge News

Although capecitabine boosted DFS by approximately 6%, overall survival remained unchanged, reported lead author Junjie Li, MD, of Fudan University in Shanghai, China.

In a presentation at the San Antonio Breast Cancer Symposium, Dr. Li explained that these findings provide much-needed support for the concomitant use of capecitabine in breast cancer.

“Capecitabine has been proven [effective] in advanced breast cancer, while in earlier stage disease, available data are still inconsistent,” Dr. Li said.

To help resolve some of this uncertainty, Dr. Li and colleagues conducted an open-label, phase 3 trial involving 585 patients with TNBC who were either node positive or negative and had tumors more than 1 cm in diameter. Patients were randomized in a 1:1 ratio to receive either standard therapy with three cycles of docetaxel followed by three cycles of cyclophosphamide, epirubicin, and fluorouracil; or three cycles of capecitabine and docetaxel followed by three cycles of cyclophosphamide, epirubicin, and capecitabine.

After a median follow-up of 67 months, 288 patients had received the capecitabine regimen and 273 had undergone standard therapy. The 5-year DFS was significantly longer in the capecitabine group, at 86.26%, than the control group, at 80.23% (hazard ratio, 0.66; P = .038). This benefit extended across subgroups, Dr. Li noted. While a slight numerical difference in overall survival was seen between capecitabine and control arms, this was not statistically significant (93.27% vs. 90.55%).

The investigators described safety profiles between treatment arms as “generally comparable.” In the capecitabine group, more than one-third of patients (38.89%) had dose reductions, while 8.42% reported grade 3-4 hand-foot syndrome. Grade 3-4 toxicities were more common in the capecitabine group, including neutropenia (45.79% vs. 41.32%) and febrile neutropenia (16.5% vs. 15.97%).

“Capecitabine concomitant use with docetaxel and epirubicin may significantly improve disease-free survival in early triple-negative patients,” Dr. Li concluded. He suggested that the study regimen be viewed as an alternative adjuvant regimen, as it provided clinically meaningful improvements in survival while maintaining tolerability.

Conference attendee Mohamed El-Naghy, MD, PhD, a practicing oncologist in Oneida, N.Y., expressed concern for one aspect of the trial methodology during the question and answer session following Dr. Li’s presentation: Although all patients in the trial were considered triple negative, 10 patients had estrogen receptor/progesterone receptor (ER/PR) expression ranging from 1 to 9%, which conflicts with the definition of TNBCr provided by current guidelines, according to Dr. Li.

“It is always important to have common language,” Dr. El-Naghy said. “And if you define [TNBC by] ER/PR negativity, and still you have 10% [expression], that is unacceptable. The whole point is, I looked at your numbers – 10 patients in the whole study – maybe you say they are triple negative, but these [patients] are contamination to your sample.”

Responding to this comment, Dr. Li said that the data from these patients had a minimal impact on the study results.

“We did another analysis to exclude these 10 patients, but still the result is quite similar, because they are just 10 patients – 5 in each group,” Dr. Li said.

Will Pass/MDedge News

Invited discussant Priyanka Sharma, MD, of the University of Kansas Medical Center, Kansas City, offered some additional viewpoints on the trial.

“A large proportion of patients had non–grade III disease, and one could say that the dose of docetaxel monotherapy in the control arm was not the traditional 100 mg/m², and that could have negatively impacted the outcomes in the control arm,” Dr. Sharma said. “In addition, the trial is representative of patients only from China, and whether these findings would hold true in other ethnic and racial groups is not known. Furthermore, there seemed to be limited efficacy in patients with N0 disease, which comprised two-thirds of the trial.”

Despite these potential limitations, based on the trial results and other evidence, Dr. Sharma suggested that adding capecitabine to standard systemic therapy may be considered a viable option for patients with early TNBC.

The investigators reported no disclosures.

SOURCE: Li J et al. SABCS 2019, Abstract GS1-08.