From the Editor

Dr. Cosgrove took the leadership reins of the Clinic in 2004, the same year Dr. Mihaljevic joined the Department of Cardiothoracic Surgery. Under Dr. Cosgrove’s leadership the Clinic has grown in size, scope of practice, and international impact. His support of education has contributed enormously to the maturation of the Cleveland Clinic Lerner College of Medicine, the continued successes of our sizeable postgraduate education training program, and many other activities including our CME Center and the Cleveland Clinic Journal of Medicine. His willingness to recognize and continue to subsidize the Journal as an educational vehicle, with no direct marketing intent, has permitted the Journal to thrive in the international medical education space as a leading purveyor of sound, practical, evidence-based medical information. I speak for our editorial staff, authors, and readers when I say, “Thank you, Toby, for your support, trust, and belief in our educational mission.”

Dr. Mihaljevic is also a notable cardiothoracic surgeon, widely recognized for his skills and expertise in innovative minimally invasive and robotic-assisted cardiac valve surgery. He has returned to our Cleveland campus after several years as CEO of Cleveland Clinic Abu Dhabi. We welcome him back in his new role.

As Cleveland Clinic leadership undergoes an expected smooth transition, healthcare in the United States seems perpetually stuck trying to balance the response to a plethora of scientific and clinical advances, the rapid technologic changes in healthcare delivery systems, the cost-profit distribution within and external to expanding healthcare systems, and divergent social and political pressures. Advances in molecular medicine are changing the diagnosis and therapy of cancers and inflammatory diseases. Personalized precision medicine is evolving from the abstract to the tangible. Surgical advances on a true macro scale are leading to deliverable, effective treatments of the metabolic manifestations of diabetes, while microscopic, intravascular, and minimally invasive approaches are transforming the management of patients with structural and infiltrative disease. Understanding of the microbiome may well lead to better management of cardiovascular and inflammatory diseases. There have been advances in tissue scaffolding as well as gene and cell replacement techniques that may soon transform the therapy of several diseases. These advances provide cause for intellectual and clinical enthusiasm.

And yet, the environment in which we live and practice is increasingly divided and divisive socially and politically. Medicine has lost much of its luster. Burnout and early retirement are adversely affecting the physician workforce. The current model of financial support for medical education in the United States is being reevaluated, without a clear effective alternative. Costs of healthcare are rising at unsustainable rates, and swathes of our vulnerable, elderly, and young middle-class population are faced with serious challenges in getting and maintaining medical care because it is inaccessible and unaffordable. Even for patients of comfortable financial means, acquiring health insurance is not an activity for the weak of heart (and that weakness might be interpreted in the future as a pre-existing condition).

Who will pay for the exciting innovations I noted above, and who will deliver them? As reimbursement is shrinking, the time demands for physician electronic charting and communications with insurance companies are increasing. More physicians are employed and controlled by healthcare systems. How many will have the time and updated knowledge to discuss the appropriateness and clinical implications of these therapies between the phone calls begging for insurance company approval of coverage and payment?

As corporate taxes appear on the brink of being reduced, we can hope that this corporate financial benefit will translate to reduced drug and device costs and more affordable insurance for our more vulnerable populations. But this is not certain.

I have concerns as to how clinical science and healthcare delivery can move forward in an environment in which federal directives now prohibit our most respected federal research agencies from using such terms as “vulnerable” (populations) and “evidence-based” to justify their proposals for budgetary support for their ongoing work in population disease health and disease management.¹ Even a short time spent in the hallways or emergency rooms of any of our safety-net hospitals reveals the strain that acute and chronic illness is imposing on the social fabric of families, society, and the often underfunded infrastructure of this aspect of our healthcare system. Who will be in the position to empathetically and objectively assess the value of translating these ongoing efforts in discovery to implementation?

Basic stem cell and genetic research is also under ongoing scrutiny. There remains legitimate fear that ultimate policy decisions will not be made by fully informed scientists and ethicists. The ongoing “dialogue” in the United States around climate change and global warming does not give me confidence that our current government policy-makers are up to the task of objectively dealing with these more nuanced and emotionally charged issues, particularly while avoiding the expression of any evidence-based rationales.

In 2016, the world lost the iconic musical poet Leonard Cohen. Hopefully, he got it right when he wrote:

Ring the bells that still can ring
Forget your perfect offering
There is a crack in everything
That’s how the light gets in
—“Anthem”; 1992

I and the rest of our editorial team wish you, our readers, a healthy and peaceful 2018. I am optimistic that we can all find or create at least some light.

Dr. Cosgrove took the leadership reins of the Clinic in 2004, the same year Dr. Mihaljevic joined the Department of Cardiothoracic Surgery. Under Dr. Cosgrove’s leadership the Clinic has grown in size, scope of practice, and international impact. His support of education has contributed enormously to the maturation of the Cleveland Clinic Lerner College of Medicine, the continued successes of our sizeable postgraduate education training program, and many other activities including our CME Center and the Cleveland Clinic Journal of Medicine. His willingness to recognize and continue to subsidize the Journal as an educational vehicle, with no direct marketing intent, has permitted the Journal to thrive in the international medical education space as a leading purveyor of sound, practical, evidence-based medical information. I speak for our editorial staff, authors, and readers when I say, “Thank you, Toby, for your support, trust, and belief in our educational mission.”

Dr. Mihaljevic is also a notable cardiothoracic surgeon, widely recognized for his skills and expertise in innovative minimally invasive and robotic-assisted cardiac valve surgery. He has returned to our Cleveland campus after several years as CEO of Cleveland Clinic Abu Dhabi. We welcome him back in his new role.

As Cleveland Clinic leadership undergoes an expected smooth transition, healthcare in the United States seems perpetually stuck trying to balance the response to a plethora of scientific and clinical advances, the rapid technologic changes in healthcare delivery systems, the cost-profit distribution within and external to expanding healthcare systems, and divergent social and political pressures. Advances in molecular medicine are changing the diagnosis and therapy of cancers and inflammatory diseases. Personalized precision medicine is evolving from the abstract to the tangible. Surgical advances on a true macro scale are leading to deliverable, effective treatments of the metabolic manifestations of diabetes, while microscopic, intravascular, and minimally invasive approaches are transforming the management of patients with structural and infiltrative disease. Understanding of the microbiome may well lead to better management of cardiovascular and inflammatory diseases. There have been advances in tissue scaffolding as well as gene and cell replacement techniques that may soon transform the therapy of several diseases. These advances provide cause for intellectual and clinical enthusiasm.

And yet, the environment in which we live and practice is increasingly divided and divisive socially and politically. Medicine has lost much of its luster. Burnout and early retirement are adversely affecting the physician workforce. The current model of financial support for medical education in the United States is being reevaluated, without a clear effective alternative. Costs of healthcare are rising at unsustainable rates, and swathes of our vulnerable, elderly, and young middle-class population are faced with serious challenges in getting and maintaining medical care because it is inaccessible and unaffordable. Even for patients of comfortable financial means, acquiring health insurance is not an activity for the weak of heart (and that weakness might be interpreted in the future as a pre-existing condition).

Who will pay for the exciting innovations I noted above, and who will deliver them? As reimbursement is shrinking, the time demands for physician electronic charting and communications with insurance companies are increasing. More physicians are employed and controlled by healthcare systems. How many will have the time and updated knowledge to discuss the appropriateness and clinical implications of these therapies between the phone calls begging for insurance company approval of coverage and payment?

As corporate taxes appear on the brink of being reduced, we can hope that this corporate financial benefit will translate to reduced drug and device costs and more affordable insurance for our more vulnerable populations. But this is not certain.

I have concerns as to how clinical science and healthcare delivery can move forward in an environment in which federal directives now prohibit our most respected federal research agencies from using such terms as “vulnerable” (populations) and “evidence-based” to justify their proposals for budgetary support for their ongoing work in population disease health and disease management.¹ Even a short time spent in the hallways or emergency rooms of any of our safety-net hospitals reveals the strain that acute and chronic illness is imposing on the social fabric of families, society, and the often underfunded infrastructure of this aspect of our healthcare system. Who will be in the position to empathetically and objectively assess the value of translating these ongoing efforts in discovery to implementation?

Basic stem cell and genetic research is also under ongoing scrutiny. There remains legitimate fear that ultimate policy decisions will not be made by fully informed scientists and ethicists. The ongoing “dialogue” in the United States around climate change and global warming does not give me confidence that our current government policy-makers are up to the task of objectively dealing with these more nuanced and emotionally charged issues, particularly while avoiding the expression of any evidence-based rationales.

In 2016, the world lost the iconic musical poet Leonard Cohen. Hopefully, he got it right when he wrote:

Ring the bells that still can ring
Forget your perfect offering
There is a crack in everything
That’s how the light gets in
—“Anthem”; 1992

I and the rest of our editorial team wish you, our readers, a healthy and peaceful 2018. I am optimistic that we can all find or create at least some light.

Dr. Cosgrove took the leadership reins of the Clinic in 2004, the same year Dr. Mihaljevic joined the Department of Cardiothoracic Surgery. Under Dr. Cosgrove’s leadership the Clinic has grown in size, scope of practice, and international impact. His support of education has contributed enormously to the maturation of the Cleveland Clinic Lerner College of Medicine, the continued successes of our sizeable postgraduate education training program, and many other activities including our CME Center and the Cleveland Clinic Journal of Medicine. His willingness to recognize and continue to subsidize the Journal as an educational vehicle, with no direct marketing intent, has permitted the Journal to thrive in the international medical education space as a leading purveyor of sound, practical, evidence-based medical information. I speak for our editorial staff, authors, and readers when I say, “Thank you, Toby, for your support, trust, and belief in our educational mission.”

Dr. Mihaljevic is also a notable cardiothoracic surgeon, widely recognized for his skills and expertise in innovative minimally invasive and robotic-assisted cardiac valve surgery. He has returned to our Cleveland campus after several years as CEO of Cleveland Clinic Abu Dhabi. We welcome him back in his new role.

As Cleveland Clinic leadership undergoes an expected smooth transition, healthcare in the United States seems perpetually stuck trying to balance the response to a plethora of scientific and clinical advances, the rapid technologic changes in healthcare delivery systems, the cost-profit distribution within and external to expanding healthcare systems, and divergent social and political pressures. Advances in molecular medicine are changing the diagnosis and therapy of cancers and inflammatory diseases. Personalized precision medicine is evolving from the abstract to the tangible. Surgical advances on a true macro scale are leading to deliverable, effective treatments of the metabolic manifestations of diabetes, while microscopic, intravascular, and minimally invasive approaches are transforming the management of patients with structural and infiltrative disease. Understanding of the microbiome may well lead to better management of cardiovascular and inflammatory diseases. There have been advances in tissue scaffolding as well as gene and cell replacement techniques that may soon transform the therapy of several diseases. These advances provide cause for intellectual and clinical enthusiasm.

And yet, the environment in which we live and practice is increasingly divided and divisive socially and politically. Medicine has lost much of its luster. Burnout and early retirement are adversely affecting the physician workforce. The current model of financial support for medical education in the United States is being reevaluated, without a clear effective alternative. Costs of healthcare are rising at unsustainable rates, and swathes of our vulnerable, elderly, and young middle-class population are faced with serious challenges in getting and maintaining medical care because it is inaccessible and unaffordable. Even for patients of comfortable financial means, acquiring health insurance is not an activity for the weak of heart (and that weakness might be interpreted in the future as a pre-existing condition).

Who will pay for the exciting innovations I noted above, and who will deliver them? As reimbursement is shrinking, the time demands for physician electronic charting and communications with insurance companies are increasing. More physicians are employed and controlled by healthcare systems. How many will have the time and updated knowledge to discuss the appropriateness and clinical implications of these therapies between the phone calls begging for insurance company approval of coverage and payment?

As corporate taxes appear on the brink of being reduced, we can hope that this corporate financial benefit will translate to reduced drug and device costs and more affordable insurance for our more vulnerable populations. But this is not certain.

I have concerns as to how clinical science and healthcare delivery can move forward in an environment in which federal directives now prohibit our most respected federal research agencies from using such terms as “vulnerable” (populations) and “evidence-based” to justify their proposals for budgetary support for their ongoing work in population disease health and disease management.¹ Even a short time spent in the hallways or emergency rooms of any of our safety-net hospitals reveals the strain that acute and chronic illness is imposing on the social fabric of families, society, and the often underfunded infrastructure of this aspect of our healthcare system. Who will be in the position to empathetically and objectively assess the value of translating these ongoing efforts in discovery to implementation?

Basic stem cell and genetic research is also under ongoing scrutiny. There remains legitimate fear that ultimate policy decisions will not be made by fully informed scientists and ethicists. The ongoing “dialogue” in the United States around climate change and global warming does not give me confidence that our current government policy-makers are up to the task of objectively dealing with these more nuanced and emotionally charged issues, particularly while avoiding the expression of any evidence-based rationales.

In 2016, the world lost the iconic musical poet Leonard Cohen. Hopefully, he got it right when he wrote:

Ring the bells that still can ring
Forget your perfect offering
There is a crack in everything
That’s how the light gets in
—“Anthem”; 1992

I and the rest of our editorial team wish you, our readers, a healthy and peaceful 2018. I am optimistic that we can all find or create at least some light.

Cholesterol generally is regarded as a cardiovascular risk factor when elevated. However, numerous studies suggest that cholesterol levels—both high and low—may be associated with various psychiatric brain disorders.¹ Thus, psychiatrists should mind their patients’ cholesterol because it may affect their minds, not just their hearts.

The relationship between cholesterol and mental illness is fascinating, complex, and perplexing. Whether elevated or reduced, cholesterol’s effects can be deleterious or salutary, but the literature is riddled with conflicting reports. Physicians should measure their patients’ serum cholesterol levels not only to assess cardiovascular risk, but because cholesterol can be associated with certain neuropsychiatric disorders or may predict the lack of response to psychopharmacotherapy.²

The fact that lowering total cholesterol levels in people with hypercholesterolemia reduces the risk of coronary heart disease is indisputable. Large-scale cardiology clinical trials have shown a significant reduction in mortality from heart disease or stroke with cholesterol-lowering drugs (statins). However, the same trials found an uptick in “unnatural deaths,” mostly suicide or homicide.³ Those findings triggered numerous intriguing reports of the association between cholesterol levels and psychopathology.

Consider the following:

• Low cholesterol levels have been associated with depression, antisocial personality disorder, borderline personality disorder, and dissociative disorder.⁴
• High cholesterol levels have been associated with schizophrenia, obsessive-compulsive disorder, panic disorder, generalized anxiety disorder, and posttraumatic stress disorder.⁴
• Some studies suggest that high cholesterol levels are associated with better mental health, mental processing speed, social skills, responsibility, self-control, and self-awareness.⁵
• In the Clinical Antipsychotic Trials of Intervention Effectiveness schizophrenia study, better cognitive scores were found in patients with higher fasting cholesterol and triglyceride levels (H.A.N., unpublished data, 2017).

The brain is only 2% of body weight, but it contains 25% of the body’s cholesterol.⁶ Cholesterol is important for brain function and neurotransmission because neuroactive steroids (NASs) are synthesized from cholesterol and they modulate brain processes and interact with γ-aminobutyric acid, N-methyl-d-aspartate, and serotonin receptors (all of which are implicated in psychiatric disorders) as well as neurotrophins such as nerve growth factor.⁷ NASs are involved in mood regulation and cognition, and regulate synaptic plasticity, apoptosis, and neuroprotection.⁷ For the brain to function normally, NASs must maintain normal levels, because low levels may lead to adverse consequences, such as depression, neuro­inflammation, epilepsy, multiple sclerosis, and psychosis. On the other hand, high levels may lead to attention-deficit/hyperactivity disorder and stress. Thus, NASs—such as pregnane, androstane, and sulfated neurosteroids, all synthesized from cholesterol—are critical molecules with major neuropsychiatric activity.⁸ This may provide clues to the mechanisms of action by which cholesterol levels influence psychiatric brain functions. Cholesterol has been described as a multipurpose molecule that is a critical component of neuronal cell membranes and a precursor for many signaling molecules.⁹

Interestingly, both extremes in cholesterol levels represent a high risk for premature mortality.¹⁰ Hyper­cholesterolemia leads to early death from coronary artery disease. Studies that evaluated statins to lower cholesterol found increased mortality from suicide, accidents, and violence.¹¹ Even without statin treatment, among persons with naturally low cholesterol, there is a significant increase in mortality from non-medical causes.¹² However, some studies did not find an association between hypocholesterolemia and suicide.^13,14

There also is some evidence that elevated cholesterol may play a role in dementia.¹⁵ Reducing cholesterol with statins decreases beta-amyloid in mice, while the opposite occurs with elevated cholesterol.² Another possible mechanism by which high cholesterol worsens dementia is that neurodegeneration in Alzheimer’s disease (AD) breaks down neuronal cell membranes, which releases the neurotoxic metabolite of cholesterol (24-hydroxycholesterol), which leads to further neurodegeneration.¹⁶ Statins may decrease the production of 24-hydroxycholesterol in AD patients and slow down neuro­degeneration.¹⁶
 

A large study of 4,444 consecutive patients in Taiwan found that those with low total cholesterol (<160 mg/dL) had higher scores of anxiety, phobia, psychoticism, and aggressive hostility.¹⁷ In the same study, women with low high-density lipoprotein cholesterol (<35 mg/dL) had significantly higher scores for depression, phobia, anxiety, interpersonal sensitivity, somatization, and aggressive hostility.¹⁷

Not surprisingly, low cholesterol has been proposed as a biomarker for mood dysregulation, depression, and suicidality,¹⁸ as well as a predictor of the depression severity and increased suicide risk.¹⁹ Clinical recovery in depression may be accompanied by a significant increase of total cholesterol²⁰ but, interestingly, a decrease in cholesterol levels after treatment of mania. High cholesterol was reported to predict poorer response to selective serotonin reuptake inhibitors, and total cholesterol levels >200 mg/dL were associated with lack of response to fluoxetine and nortriptyline.² Interestingly, clozapine, which elevates lipids, exerts a strong anti-suicide effect in schizophrenia and schizoaffective disorder, but that may not be the main reason for its efficacy in preventing suicide in patients with psychosis.

Cholesterol is an important lipid for brain function. At lower levels, it appears to be associated with depression, suicide, violence, anxiety, schizophrenia, and severe personality disorders (including antisocial personality disorder and borderline personality disorder). However, at high levels, it may improve cognition in schizophrenia and ameliorate the pace of AD and neurodegeneration. Psychiatrists should monitor patients for hypercholesterolemia and hypocholesterolemia, both of which are common among psychiatric patients. High levels may be genetic or the result of weight gain, hypercortisolemia, diabetes, or immune or inflammatory processes. Similarly, low levels may be genetic or secondary to statin therapy.

The bottom line: As psychiatric physicians, we should protect both the hearts and brains of our patients.

Cholesterol generally is regarded as a cardiovascular risk factor when elevated. However, numerous studies suggest that cholesterol levels—both high and low—may be associated with various psychiatric brain disorders.¹ Thus, psychiatrists should mind their patients’ cholesterol because it may affect their minds, not just their hearts.

The relationship between cholesterol and mental illness is fascinating, complex, and perplexing. Whether elevated or reduced, cholesterol’s effects can be deleterious or salutary, but the literature is riddled with conflicting reports. Physicians should measure their patients’ serum cholesterol levels not only to assess cardiovascular risk, but because cholesterol can be associated with certain neuropsychiatric disorders or may predict the lack of response to psychopharmacotherapy.²

The fact that lowering total cholesterol levels in people with hypercholesterolemia reduces the risk of coronary heart disease is indisputable. Large-scale cardiology clinical trials have shown a significant reduction in mortality from heart disease or stroke with cholesterol-lowering drugs (statins). However, the same trials found an uptick in “unnatural deaths,” mostly suicide or homicide.³ Those findings triggered numerous intriguing reports of the association between cholesterol levels and psychopathology.

Consider the following:

• Low cholesterol levels have been associated with depression, antisocial personality disorder, borderline personality disorder, and dissociative disorder.⁴
• High cholesterol levels have been associated with schizophrenia, obsessive-compulsive disorder, panic disorder, generalized anxiety disorder, and posttraumatic stress disorder.⁴
• Some studies suggest that high cholesterol levels are associated with better mental health, mental processing speed, social skills, responsibility, self-control, and self-awareness.⁵
• In the Clinical Antipsychotic Trials of Intervention Effectiveness schizophrenia study, better cognitive scores were found in patients with higher fasting cholesterol and triglyceride levels (H.A.N., unpublished data, 2017).

The brain is only 2% of body weight, but it contains 25% of the body’s cholesterol.⁶ Cholesterol is important for brain function and neurotransmission because neuroactive steroids (NASs) are synthesized from cholesterol and they modulate brain processes and interact with γ-aminobutyric acid, N-methyl-d-aspartate, and serotonin receptors (all of which are implicated in psychiatric disorders) as well as neurotrophins such as nerve growth factor.⁷ NASs are involved in mood regulation and cognition, and regulate synaptic plasticity, apoptosis, and neuroprotection.⁷ For the brain to function normally, NASs must maintain normal levels, because low levels may lead to adverse consequences, such as depression, neuro­inflammation, epilepsy, multiple sclerosis, and psychosis. On the other hand, high levels may lead to attention-deficit/hyperactivity disorder and stress. Thus, NASs—such as pregnane, androstane, and sulfated neurosteroids, all synthesized from cholesterol—are critical molecules with major neuropsychiatric activity.⁸ This may provide clues to the mechanisms of action by which cholesterol levels influence psychiatric brain functions. Cholesterol has been described as a multipurpose molecule that is a critical component of neuronal cell membranes and a precursor for many signaling molecules.⁹

Interestingly, both extremes in cholesterol levels represent a high risk for premature mortality.¹⁰ Hyper­cholesterolemia leads to early death from coronary artery disease. Studies that evaluated statins to lower cholesterol found increased mortality from suicide, accidents, and violence.¹¹ Even without statin treatment, among persons with naturally low cholesterol, there is a significant increase in mortality from non-medical causes.¹² However, some studies did not find an association between hypocholesterolemia and suicide.^13,14

There also is some evidence that elevated cholesterol may play a role in dementia.¹⁵ Reducing cholesterol with statins decreases beta-amyloid in mice, while the opposite occurs with elevated cholesterol.² Another possible mechanism by which high cholesterol worsens dementia is that neurodegeneration in Alzheimer’s disease (AD) breaks down neuronal cell membranes, which releases the neurotoxic metabolite of cholesterol (24-hydroxycholesterol), which leads to further neurodegeneration.¹⁶ Statins may decrease the production of 24-hydroxycholesterol in AD patients and slow down neuro­degeneration.¹⁶
 

A large study of 4,444 consecutive patients in Taiwan found that those with low total cholesterol (<160 mg/dL) had higher scores of anxiety, phobia, psychoticism, and aggressive hostility.¹⁷ In the same study, women with low high-density lipoprotein cholesterol (<35 mg/dL) had significantly higher scores for depression, phobia, anxiety, interpersonal sensitivity, somatization, and aggressive hostility.¹⁷

Not surprisingly, low cholesterol has been proposed as a biomarker for mood dysregulation, depression, and suicidality,¹⁸ as well as a predictor of the depression severity and increased suicide risk.¹⁹ Clinical recovery in depression may be accompanied by a significant increase of total cholesterol²⁰ but, interestingly, a decrease in cholesterol levels after treatment of mania. High cholesterol was reported to predict poorer response to selective serotonin reuptake inhibitors, and total cholesterol levels >200 mg/dL were associated with lack of response to fluoxetine and nortriptyline.² Interestingly, clozapine, which elevates lipids, exerts a strong anti-suicide effect in schizophrenia and schizoaffective disorder, but that may not be the main reason for its efficacy in preventing suicide in patients with psychosis.

Cholesterol is an important lipid for brain function. At lower levels, it appears to be associated with depression, suicide, violence, anxiety, schizophrenia, and severe personality disorders (including antisocial personality disorder and borderline personality disorder). However, at high levels, it may improve cognition in schizophrenia and ameliorate the pace of AD and neurodegeneration. Psychiatrists should monitor patients for hypercholesterolemia and hypocholesterolemia, both of which are common among psychiatric patients. High levels may be genetic or the result of weight gain, hypercortisolemia, diabetes, or immune or inflammatory processes. Similarly, low levels may be genetic or secondary to statin therapy.

The bottom line: As psychiatric physicians, we should protect both the hearts and brains of our patients.

Cholesterol generally is regarded as a cardiovascular risk factor when elevated. However, numerous studies suggest that cholesterol levels—both high and low—may be associated with various psychiatric brain disorders.¹ Thus, psychiatrists should mind their patients’ cholesterol because it may affect their minds, not just their hearts.

The relationship between cholesterol and mental illness is fascinating, complex, and perplexing. Whether elevated or reduced, cholesterol’s effects can be deleterious or salutary, but the literature is riddled with conflicting reports. Physicians should measure their patients’ serum cholesterol levels not only to assess cardiovascular risk, but because cholesterol can be associated with certain neuropsychiatric disorders or may predict the lack of response to psychopharmacotherapy.²

The fact that lowering total cholesterol levels in people with hypercholesterolemia reduces the risk of coronary heart disease is indisputable. Large-scale cardiology clinical trials have shown a significant reduction in mortality from heart disease or stroke with cholesterol-lowering drugs (statins). However, the same trials found an uptick in “unnatural deaths,” mostly suicide or homicide.³ Those findings triggered numerous intriguing reports of the association between cholesterol levels and psychopathology.

Consider the following:

• Low cholesterol levels have been associated with depression, antisocial personality disorder, borderline personality disorder, and dissociative disorder.⁴
• High cholesterol levels have been associated with schizophrenia, obsessive-compulsive disorder, panic disorder, generalized anxiety disorder, and posttraumatic stress disorder.⁴
• Some studies suggest that high cholesterol levels are associated with better mental health, mental processing speed, social skills, responsibility, self-control, and self-awareness.⁵
• In the Clinical Antipsychotic Trials of Intervention Effectiveness schizophrenia study, better cognitive scores were found in patients with higher fasting cholesterol and triglyceride levels (H.A.N., unpublished data, 2017).

The brain is only 2% of body weight, but it contains 25% of the body’s cholesterol.⁶ Cholesterol is important for brain function and neurotransmission because neuroactive steroids (NASs) are synthesized from cholesterol and they modulate brain processes and interact with γ-aminobutyric acid, N-methyl-d-aspartate, and serotonin receptors (all of which are implicated in psychiatric disorders) as well as neurotrophins such as nerve growth factor.⁷ NASs are involved in mood regulation and cognition, and regulate synaptic plasticity, apoptosis, and neuroprotection.⁷ For the brain to function normally, NASs must maintain normal levels, because low levels may lead to adverse consequences, such as depression, neuro­inflammation, epilepsy, multiple sclerosis, and psychosis. On the other hand, high levels may lead to attention-deficit/hyperactivity disorder and stress. Thus, NASs—such as pregnane, androstane, and sulfated neurosteroids, all synthesized from cholesterol—are critical molecules with major neuropsychiatric activity.⁸ This may provide clues to the mechanisms of action by which cholesterol levels influence psychiatric brain functions. Cholesterol has been described as a multipurpose molecule that is a critical component of neuronal cell membranes and a precursor for many signaling molecules.⁹

Interestingly, both extremes in cholesterol levels represent a high risk for premature mortality.¹⁰ Hyper­cholesterolemia leads to early death from coronary artery disease. Studies that evaluated statins to lower cholesterol found increased mortality from suicide, accidents, and violence.¹¹ Even without statin treatment, among persons with naturally low cholesterol, there is a significant increase in mortality from non-medical causes.¹² However, some studies did not find an association between hypocholesterolemia and suicide.^13,14

There also is some evidence that elevated cholesterol may play a role in dementia.¹⁵ Reducing cholesterol with statins decreases beta-amyloid in mice, while the opposite occurs with elevated cholesterol.² Another possible mechanism by which high cholesterol worsens dementia is that neurodegeneration in Alzheimer’s disease (AD) breaks down neuronal cell membranes, which releases the neurotoxic metabolite of cholesterol (24-hydroxycholesterol), which leads to further neurodegeneration.¹⁶ Statins may decrease the production of 24-hydroxycholesterol in AD patients and slow down neuro­degeneration.¹⁶
 

A large study of 4,444 consecutive patients in Taiwan found that those with low total cholesterol (<160 mg/dL) had higher scores of anxiety, phobia, psychoticism, and aggressive hostility.¹⁷ In the same study, women with low high-density lipoprotein cholesterol (<35 mg/dL) had significantly higher scores for depression, phobia, anxiety, interpersonal sensitivity, somatization, and aggressive hostility.¹⁷

Not surprisingly, low cholesterol has been proposed as a biomarker for mood dysregulation, depression, and suicidality,¹⁸ as well as a predictor of the depression severity and increased suicide risk.¹⁹ Clinical recovery in depression may be accompanied by a significant increase of total cholesterol²⁰ but, interestingly, a decrease in cholesterol levels after treatment of mania. High cholesterol was reported to predict poorer response to selective serotonin reuptake inhibitors, and total cholesterol levels >200 mg/dL were associated with lack of response to fluoxetine and nortriptyline.² Interestingly, clozapine, which elevates lipids, exerts a strong anti-suicide effect in schizophrenia and schizoaffective disorder, but that may not be the main reason for its efficacy in preventing suicide in patients with psychosis.

Cholesterol is an important lipid for brain function. At lower levels, it appears to be associated with depression, suicide, violence, anxiety, schizophrenia, and severe personality disorders (including antisocial personality disorder and borderline personality disorder). However, at high levels, it may improve cognition in schizophrenia and ameliorate the pace of AD and neurodegeneration. Psychiatrists should monitor patients for hypercholesterolemia and hypocholesterolemia, both of which are common among psychiatric patients. High levels may be genetic or the result of weight gain, hypercortisolemia, diabetes, or immune or inflammatory processes. Similarly, low levels may be genetic or secondary to statin therapy.

The bottom line: As psychiatric physicians, we should protect both the hearts and brains of our patients.

This past year will likely be remembered as one of breakthrough advances in reducing the burden of cancer, with some landmark “firsts” coming out of the US Food and Drug Administration (FDA). Among the notable approvals were the first CART [chimeric antigen receptor T-cell] immunotherapies – tisagenlecleucel (Kymriah) for B-cell precursor acute lymphoblastic leukemia, and axicabtagene ciloleucel (Yescarta) for relapsed or refractory large B-cell lymphoma; the first US-approved biosimilar for cancer, bevacizumab-awwb (Mvasi) for multiple types of cancer; and first-time approvals for neratinib (Nerlynx) as an extended adjuvant therapy for early-stage human epidermal growth factor receptor 2 (HER2)-overexpressed/amplified breast cancer, and avelumab (Bavencio) for the treatment of metastatic Merkel cell carcinoma. But our excitement about those advances will undoubtedly be tempered by the continued challenges in expanding access to better quality health care, piloting more effective payment models, and consolidating delivery systems.

Our excitement has also been tempered by the rapid rise in the cost of effective biologic, immunologic, and targeted therapies. With the approval of trastuzumab-dkst (Ogivri), the first targeted biosimilar for HER2-positive breast and gastrointestinal cancers, we can look forward to price decreases possibly in the 20%-30% range over time from a targeted therapy with remarkable clinical efficacy. We know that approved biosimilars have demonstrated clinical efficacy along with similar minor biologic diversity that is also seen in the reference biologic.¹ We can also hope that increasing competition among biosimilar and reference compounds will lead to improvements in production methodologies that can allow further price reductions so that even more patients can gain access to these highly effective therapies.

In addition, the first FDA approval for the next-generation sequencing (NGS) FoundationOne profiling test and the rapid announcement by the Centers for Medicare & Medicaid Services (CMS) that it will cover the cost of that testing brings us a step closer to knowing which patients most likely will or won’t benefit from costly and toxic targeted therapies. Along with the many clinical trials studying which mutations predict which efficacies of individual or combinations of targeted agents, the approval and CMS coverage policy will help us improve value to our patients; when we can recommend the most beneficial therapies and avoid futile ones.

Finally, the approval for the DigniCap Scalp Cooling System for patients on chemotherapy for all solid tumors is of great importance. Pending coverage availability, it may influence some patients to get chemotherapy they might otherwise have forgone to avoid hair loss (see related article).

More consolidation: the best of all worlds?

In my 27 years in private practice, during which practice revenues grew with the favorable profit margins on novel therapies, forward-thinking physician leaders piloted innovations in oncology electronic medical records (EMRs), the delivery of team-based care, clinical research partnerships, and more comprehensive care services to better serve diverse communities, including those in rural areas. At my previous practice, that included adding clinicians to our group to serve patients at hospital clinics in 2 counties in southern California, each county with populations larger than 15 states. Our private practice worked with these public entities to bring state-of-the art care and private practice efficiencies to the uninsured and underserved in our region.

Unfortunately, revenues plummeted with changes in reimbursement after passage of the Medicare Modernization Act in 2003 and they continue to destabilize and reduce the number of community practices across the country. Many oncologists and oncology practices, including mine, chose to join larger academic or hospital systems or larger oncology networks at a time they are also facing growing pressures to contain costs, focus on out-patient care, complex clinical trials, and expanded access to care.

Although we may lament the shrinking landscape of private oncology practices, we can also be inspired by the physicians who have joined ranks with the better-funded, better-resourced, more traditional hospital and academic systems. These larger systems have more resources, more clincial trial offerings, staffing, technology, and analytics to expand value-based care initiatives to larger numbers of patients.

The hub-and-spoke models of oncology care with integrated networks linked by technology, and networked into larger analytic and decision support systems such as CancerLinQ, the health information technology program of the American Society of Clinical Oncology (ASCO),² could facilitate documentable delivery of comprehensive, evidence-based care, moving us closer to meeting the Quadruple Aim of optimal health care: improving the patient experience of care (including quality and satisfaction); improving the health of populations; reducing the per capita cost of health care; and improving the work life of those who deliver care.^3,4

Payment reform: working to align incentives

Everyone seems to agree that the fee-for-service payment models do not align incentives for improving total health outcomes at the lowest costs, but at the moment, there seems to be no best way of aligning them. Robinson has reported on the oncology payment initiatives at four major health insurance plans – Medicare (public) and Anthem, Aetna, and UnitedHealthcare (all private), noting that:⁵

• Medicare is testing its Oncology Care Model at more than 200 sites in the United States, and early data are expected to be released in 2018.
• Anthem continues with its Cancer Care Quality Program that includes adherence to 2 key requirements: that participants are compliant with Anthem-approved drug pathways, and that they register their patients at the insurer’s oncology website and enter their clinical data. Anthem is also considering expanding the management fee for certain high priority clinical trials.
• Aetna’s Oncology Solutions takes a different approach by providing increased payments for generic chemotherapies.
• United has eliminated the mark-up for new drugs and continues to mark up the prices of the older and generic therapies. Its episode-based pricing gives practices upfront payments based on expected drug margins so that practices can fund more comprehensive evidence-based care. In a presentation at a Washington State Medical Oncology Society meeting recently, United’s Lee Newcomer, reported that the insurer continues to see improved clinical and financial outcomes as well as encouraging early data showing that patients might do better in the real-world setting on some therapies that have not been fully compared in head-to-head randomized clinical trials.^6,7

ASCO is pulling these ideas together at the national level with its Patient-Centered Oncology Payment (PCOP) model, which is similar to Medicare’s alternative payment model. The PCOP model focuses on high-value, quality care. Higher upfront payments would cover the additional diagnostic services, care planning, and management to improve compliance and adherence as well as clinical trial evaluations. The model was developed and vetted by the ASCO Clinical Practice Committee and practicing oncologists, and is supported by staff and consultants. It is currently in its second year of operation with a commercial payer and will be submitted for review to the Physician-Focused Payment Model Technical Advisory Committee of the Health and Human Services. The results of the review are expected in 2018. If the model is approved, it could provide a uniform approach for payers that would align incentives for high-quality cancer care and allow for better predictive modeling for practices, irrespective of size, to invest in infrastructure and staffing to meet the growing demand for high-quality, value-based cancer care.

Better science: the promise of more cures

The FDA approved a record number drugs and biologics in 2017 for various cancers,⁸ including the landmark approval of the first CART therapy for cancer, tisagenlecleucel, which targets CD19 on B cells in the treatment of acute leukemia. That approval was rapidly followed by a second anti-CD19 CART therapy, axicabtagene ciloluecel, for refractory, aggressive B-cell non-Hodgkin lymphoma.^9,10 Although these therapies can achieve remarkable response and even complete response rates in otherwise refractory patients, only some achieve a long-term remission, and the costs are an order of magnitude above most other cancer therapies. That raises the question of what duration of benefit we should expect for treatments that cost in the range of $500,000 for the therapy alone, along with the additional costs for care, hospitalization, monitoring, expensive biologics (eg, tocilizumab, for the severe and potentially life-threatening cytokine-release syndrome associated with CART therapies), and significant neurologic and other therapy-related toxicities.

Novel arrangements between pharmaceutical companies and payers are currently being discussed so that only patients who meet specific response criteria would be charged for the therapy. In addition, we await findings from ongoing research to see if new approaches can find specific targetable sites on solid tumors that could spare the healthy organ tissues while eliminating highly resistant or heterogeneous populations of mutations in patients with advanced solid tumors. Such development of highly specific targets for CART therapies would improve their efficacy and safety, and with defined protocols in place to address toxicities and efforts to reduce the costs of the therapies, we can hopefully ensure broader access for patients to this potentially transformative therapeutic tool.

In addition to the excitement around the CART therapies, many of the years other new approvals will bring incremental but meaningful improvement in outcomes for patients with common cancers. The approval of neratinib, the first agent approved as extended adjuvant therapy for women with early-stage HER2/neu-positive breast cancer, is welcome, given the current 30% recurrence risk that extends past 10 years for women in that disease population who have completed standard adjuvant HER2-directed therapies. The 34% reduction in recurrence risk with a year of extended oral adjuvant therapy, as reported by Martin and colleagues,¹¹ with benefits sustained out to 5 years and with controllable diarrhea as the major toxicity, are encouraging. This oral therapy may be especially beneficial for hormone-receptor–positive women in whom blocking the HER2/neu pathway may enhance cell signaling through the hormone pathways, which can be blocked with oral agents at the same time to provide significant reduction of recurrence risk.

Diagnostics

The concept of personalized medicine is based on identifying biomarkers that are predictive of a patient’s response to treatment. There has been much progress toward applying NGS of tumors for use in the clinic, but we are still awaiting evidence from randomized clinical trials that such approaches prolong overall or progression-free survival.¹² Dr Julie Lange, an associate professor of clinical surgery and director of the Breast Cancer Program at the Keck School of Medicine at the University of Southern California, Los Angeles, provided me with the references to key studies in this field in which she is a leading researcher.¹³ However, she pointed out that in the absence of effective therapies, advanced biomarker testing may be less helpful, as is the case in heavily pretreated patients,¹⁴ unless a molecular test can pinpoint a potentially clinically actionable mutation. With the plethora of available assays and the high costs of molecular testing, clinicians are challenged in knowing what testing is best for which patients. Findings from a number of key ongoing national trials may eventually help us understand which tumor mutations in which tumor types can be most effectively targeted when multiple targetable mutations are found (TAPUR,¹⁵ MATCH,¹⁶ and QUILT¹⁷ and other basket trials¹⁸). The complexity of molecular testing has led to the development of institutional, trial-based, or co-operative group molecular tumor boards to provide guidance on specific targeted therapies for specific tumor mutations.

ASCO has launched a monthly series called Molecular Oncology Tumor Boards¹⁹ to expand the knowledge base in this field. It is presented as user-driven discussions designed to help providers integrate the use of the new genetic and genomic tests and their results into the day-to-day clinical care of patients with cancer.²⁰

Liquid biopsies

As busy clinicians, we need to understand the differences in liquid biopsy tests and their correlation with actionable targets, especially given the rapid progress in this field. Again, Dr Lange offered clarity on those differences. Liquid biopsy, refers to using a blood draw to isolate circulating tumor cells (CTCs) or circulating tumor DNA (ctDNA) to assess tumor biomarkers.²¹ Both CTCs and ctDNA tests have been shown to be prognostic of worse survival.^22-24 Liquid biopsies are currently supplemental to direct tumor biopsies, not replacements for them. The theoretical advantage of liquid biopsies is that they may reflect tumor heterogeneity by examining the repertoire of mutations contributed by diverse metastatic sites that shed CTCs or ctDNA into the circulation. The question is which type of testing can best inform therapy decisions.

Assays for ctDNA using droplet digital PCR [polymerase chain reaction], a digital PCR method based on water-oil emulsion droplet technology, require a priori knowledge of the specific mutation associated with response or lack of response to a specific therapy.^25,26 Technical issues related to the detection of rare alleles present within a mixed population of leukocytes, and ctDNA remains a challenge for many ctDNA assays. However, there is evidence to suggest that whole-exome sequencing of ctDNA is concordant with mutations in metastases,²⁷ however benchmarking ctDNA against tissue biopsies of metastases was not possible in all studies because tumor blocks were not available or because of the failure of tumor NGS assays. ^28,29

Newer generations of CTC assays take advantage of the circulating tumor cell as a functional assay for mutational status, gene expression, proteomics, epigenetics, and/or chemosensitivity of cultured cells. The relationship between CTCs and ctDNA remains uncertain as to whether CTCs are the cell of origin for ctDNA or if ctDNA may reflect responding or resistant tumor populations. The use of NGS on tumor specimens, ctDNA, and CTCs as a discovery tool is advancing the field by improving the understanding of disease heterogeneity and potential treatment targets. These results require correlation with patterns of response to therapy, and ultimately require validation in randomized clinical trials to provide strong evidence justifying their use outside of clinical trials. We can look forward to a time in the not distant future when specific liquid biopsy assays will reflect the array of mutations in different metastatic sites with validation that they correlate with efficacy of targeting those mutations that have targetable therapies.

From the FDA

New approvals

• Trastuzumab-dkst (Ogivri, Mylan; Dec 1) was approved as a biosimilar to trastuzumab (Herceptin, Genentech) for the treatment of patients with HER2-overexpressing breast or metastatic stomach cancer (gastric or gastroesophageal junction adenocarcinoma).
• Sunitinib malate (Sutent, Pfizer; Nov 16) was approved for the adjuvant treatment of adult patients at high risk of recurrent renal cell carcinoma after nephrectomy.
• Obinutuzumab (Gazyva, Genentech; Nov 16) received regular approval in combination with chemotherapy, followed by obinutuzumab monotherapy in patients achieving partial remission, for adult patients with previously untreated stage II bulky, III, or IV follicular lymphoma.
• Emicizumab-kxwh (Hemlibra, Genentech; Nov 16) was approved for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A with factor VIII inhibitors.
• Dasatinib (Sprycel, Bristol-Myers Squibb; Nov 9) was approved for the treatment of pediatric patients with Philadelphia chromosome-positive chronic myeloid leukemia (CML) in the chronic phase.
• Brentuximab vedotin (Adcetris, Seattle Genetics; Nov 9) for the treatment of previously treated adult patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides.
• Alectinib (Alecensa, Hoffmann-La Roche/Genentech; Nov 6) was approved for treatment of patients with anaplastic lymphoma kinase–positive metastatic non-small cell lung cancer (NSCLC), as detected by an FDA-approved test.
• Vemurafenib (Zelboraf, Hoffmann-La Roche; Nov 6) received approval for the treatment of Acalabrutinib (Calquence, AstraZeneca/Acerta; Oct 31) was granted accelerated approval for treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one previous therapy.
• Axicabtagene ciloleucel (Yescarta, Kite; Oct 18), a CART therapy, was approved for treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. The complete remission rate reviewed by the FDA for trial patients was 51%.³⁰ It was the second CART therapy this year to receive approval (see tisagenlecleucel; Aug 30). The agency granted orphan drug designation and priority review to therapy for this indication.
• Abemaciclib (Verzenio, Eli Lilly; Sep 28) was approved in combination with fulvestrant for women with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy.
• Copanlisib (Aliqopa, Bayer; Sep 14) got accelerated approval for the treatment of adult patients with relapsed follicular lymphoma who have received at least two prior systemic therapies.
• Bevacizumab-awwb (Mvasi, Amgen; Sep 14) was approved as a biosimilar to bevacizumab (Avastin, Genentech) for treating multiple types of cancer. It was the first biosimilar approved in the US for the treatment of cancer.
• Gemtuzumab ozogamicin (Mylotarg, Pfizer; Sep 1) was approved for the treatment of newly diagnosed CD33-positive acute myeloid leukemia (AML) in adults and of relapsed/refractory CD33-positive AML in adults and pediatric patients aged 2 or older. It can be used in combination with daunorubicin and cytarabine for adults with newly diagnosed AML, or as a standalone treatment for certain adult and pediatric patients. The drug was originally approved in 2000 as a standalone treatment for CD33-positive AML in patients older than 60 years, but was withdrawn in 2010 because of safety concerns and postmarketing trials could not confirm benefit. The current approval is for a lower recommended dose and schedule.³¹
• Tisagenlecleucel (Kymriah, Novartis; Aug 30) was approved for the treatment of patients up to age 25 years with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. It is the first CART immunotherapy approved by the agency.
• Inotuzumab ozogamicin (Besponsa, Wyeth; Aug 17) was approved for the treatment of adults with relapsed or refractory B-cell precursor ALL.
• A liposome-encapsulated combination of daunorubicin and cytarabine (Vyxeos, Jazz; Aug 3) was approved for the treatment of adults with newly diagnosed therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC), two types of AML having a poor prognosis.
• Enasidenib (Idhifa, Celgene; Aug 1) was approved for the treatment of adult patients with relapsed or refractory AML with an isocitrate dehydrogenase-2 mutation as detected by an FDA-approved test.
• Neratinib (Nerlynx, Puma; Jul 17) was approved as the first extended adjuvant therapy for adult patients with early stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy.
• Blinatumomab (Blincyto, Amgen; Jul 11) was approved for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia in adults and children.
• L-glutamine oral powder (Endari, Emmaus; Jul 7) was approved for oral administration to reduce the acute complications of sickle cell disease in adult and pediatric patients 5 years and older.
• Betrixaban (Bevyxxa, Portola; Jun 23) was approved for the prophylaxis of venous thromboembolism (VTE) in adult patients hospitalized for an acute medical illness who are at risk for thromboembolic complications because of moderate or severe restricted mobility and other risk factors for VTE.
• The combination of rituximab and hyaluronidase human (Rituxan Hycela, Genentech; Jun 22) was approved for adult patients with follicular lymphoma, DLBCL, and chronic lymphocytic leukemia. Hyaluronidase human is an enzyme that helps deliver the rituximab. This formulation allows subcutaneous administration of the combination, which will shorten patient visit times and potentially even allow at-home therapy delivery.
• Ceritinib (Zykadia, Novartis; May 26) was approved for patients with metastatic NSCLC whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.
• Avelumab (Bavencio, EMD Serono; May 9) got accelerated approval for patients with locally advanced or metastatic urothelial carcinoma whose disease progressed during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.
• Durvalumab (ImfinzI, AstraZeneca; May 1) got accelerated approval for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
• Brigatinib (Alunbrig tablets, Takeda through Ariad; Apr 28) got accelerated approval for the treatment of patients with metastatic anaplastic lymphoma kinase (ALK)-positive NSCLC who have progressed on or are intolerant to crizotinib.
• Midostaurin (Rydapt, Novartis; Apr 28) was approved for the treatment of adult patients with newly diagnosed AML who are FLT3 mutation-positive, as detected by an FDA-approved test, in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation.
• Osimertinib (Tagrisso, AstraZeneca; Mar 30) got regular approval for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive NSCLC, as detected by an FDA-approved test, whose disease has progressed on or after EGFR tyrosine-kinase inhibitor therapy.
• Niraparib (Zejula, Tesaro; Mar 27), a poly ADP-ribose polymerase (PARP) inhibitor, was approved for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy.
• Avelumab (Mar 23), a PD-L1–blocking human IgG1 lambda monoclonal antibody, got accelerated approval for the treatment of patients 12 years and older with metastatic Merkel cell carcinoma. It is the first FDA-approved product to treat this type of cancer.
• Ribociclib (Kisqali, Novartis; Mar 13), a CDK4/6 inhibitor, was approved as a breakthrough therapy after priority review for use in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer.

Expanded/additional indications

• Nivolumab (Opdivo, Bristol-Myers Squibb; Sep 22) got accelerated expanded indication approval for treatment of hepatocellular carcinoma (HCC) in patients previously treated with sorafenib.
• Pembrolizumab (Keytruda, Merck; Sep 22) got accelerated expanded indication approval for recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma in patients whose tumors express PD-L1 as determined by an FDA-approved test.
• DigniCap Scalp Cooling System (Dignitana Inc; Jul 3) was cleared for expanded use for reducing hair loss during chemotherapy for all solid tumors. Marketing authorization for the cooling cap had been granted in 2015 for patients with breast cancer.
• Olaparib tablets (Lynparza, AstraZeneca; Aug 17) got approval for an expanded indication as maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in a complete or partial response to platinum-based chemotherapy.
• Ibrutinib (Imbruvica, Pharmacyclics; Aug 2) got expanded indication approval for the treatment of adult patients with chronic graft-versus-host disease (cGVHD) after failure of one or more lines of systemic therapy. It was the first FDA-approved therapy for the treatment of cGVHD. (Ibrutinib was previously approved for chronic lymphocytic leukemia/small lymphocytic lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma with 17p deletion, Waldenström’s macroglobulinemia, marginal zone lymphoma, and mantle cell lymphoma).
• Nivolumab (Aug 2) got an accelerated expanded indication for the treatment of patients 12 years and older with mismatch repair deficient (dMMR) and microsatellite instability-high (MSI-H) metastatic colorectal cancer that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
• Dabrafenib and trametinib (Tafinlar and Mekinist, Novartis; Jun 22) were approved for the expanded indication in combination for patients with metastatic NSCLC with BRAF V600E mutation as detected by an FDA-approved test. The combination demonstrated superior efficacy compared with dabrafenib alone (overall response rate: 61% and 27%, respectively).³²
• Pembrolizumab (May 23) got approved for expanded indication for adult and pediatric patients with unresectable or metastatic, MSI-H or dMMR solid tumors that have progressed after treatment and who have no satisfactory alternative treatment options or with MSI-H or dMMR colorectal cancer that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
• Pembrolizumab (May 18) got approval for expanded indication for patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
• Pembrolizumab (May 10) got accelerated expanded indication for use combination with pemetrexed and carboplatin for the treatment of patients with previously untreated metastatic NSCLC.
• Regorafenib (Stivarga, Bayer; Apr 27) got an additional indication for the treatment of patients with HCC who have been previously treated with sorafenib.
• Palbociclib (Ibrance, Pfizer; Mar 31) got an expanded indication that includes first-line therapy for the treatment of hormone receptor–positive, HER2-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine based therapy in postmenopausal women.
• Pembrolizumab (Mar 15) got an accelerated additional indication approval for treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma, or those who have relapsed after three or more previous lines of therapy.
• Lenalidomide (Revlimid, Celgene; Feb 22) got an additional indication as maintenance therapy for patients with multiple myeloma following autologous stem cell transplant.
• Nivolumab (Feb 2) got an accelerated expanded indication for treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with a platinum-containing chemotherapy.

Modified use

• Cabazitaxel (Jevtana, Sanofi-Aventis; Sep 14) in combination with prednisone was approved at a lower dose of 20 mg/m² every 3 weeks for the treatment of patients with metastatic castration-resistant prostate cancer previously treated with a docetaxel-containing treatment regimen. It had been approved at 25 mg/m² every 3 weeks for this indication in 2010.

Tests/diagnostics

• Marketing approval was given to the FoundationOne CDx (Foundation Medicine; Nov 30), an NGS-based in vitro diagnostic to detect genetic mutations in 324 genes and 2 genomic signatures in any solid tumor type.
• Marketing approval was given to the Praxis Extended RAS Panel (Illumina; Jun 29), a next generation sequencing test to detect certain genetic mutations in RAS genes in tumor samples of patients with metastatic colorectal cancer. The test is used to aid in the identification of patients who may be eligible for treatment with panitumumab (Vectibix, Amgen).
• Marketing was approved for ipsogen JAK2 RGQ PCR Kit (Qiagen ; Mar 27) to detect mutations affecting the Janus tyrosine kinase 2 gene. This is the first FDA-authorized test intended to help physicians in evaluating patients for suspected polycythemia vera.

Imaging and pathology aids

• Aminolevulinic acid hydrochloride, known as ALA HCl (Gleolan, NX; Jun 6) was approved as an optical imaging agent indicated in patients with gliomas (suspected World Health Organization grades III or IV on preoperative imaging) as an adjunct for the visualization of malignant tissue during surgery.
• Marketing was approved for the Philips IntelliSite Pathology Solution (PIPS, Philips Medical Systems Nederland; Apr 17), as an aid to the pathologist to review and interpret digital images of surgical pathology slides prepared from formalin-fixed paraffin embedded tissue.
   

Challenges and uncertainties

The current administration’s initiatives to reduce administrative burdens is underway with the Patients Over Paperwork initiative. Eliminating and streamlining regulations to increase efficiency and improve beneficiary experience could be helpful to both oncologists and patients. For now, the Medicare Access and CHIP Reauthorization Act (MACRA) program, allows you to “pick your pace” in the 2017 performance year and report on at least one measure to avoid a payment reduction penalty on your Medicare payments in 2019. In the final rule for 2018, the CMS finalized a proposal to apply the MIPS [Merit-based Incentive Payment System] adjustment to all Part B items and services, which will include Part B drugs. This would be unfair to oncologists who treat on the basis of evidence-based guidelines and pathways and have no control over the costs of the drugs they prescribe.

In addition, more requirements will be imposed in 2018 in a move toward full MACRA implementation. All four composite categories (Quality – 60% for 2017; Advancing Care Information (ACI, renamed from Meaningful Use) – 25% for 2017; Improvement Activities (IA) – 15% for 2017; and Cost – 0% for 2017, but weighted in the future) will be scored, including resource use (cost) at 10%. CMS will collect data to assess the total cost of care and the Medicare Spend per Beneficiary to assess use. Full program implementation, with cost being assessed at 30% of your score is expected in the 2019 performance year. ASCO’s clinical affairs and policy experts have studied the implications of Part B chemotherapy drugs being included in the cost component of the MIPS scoring and will continue advocating for policies that hold clinicians responsible only for the aspects of care they can control, such as providing high-quality care based on the patient’s disease, biomarkers, comorbidities, and preferences, and not the costs of the evidence-based therapies needed by patients.
 

Toward a better 2018 for ourselves and our patients

As an eternal optimist, I remain enthusiastic that despite the many challenges, we will find effective ways to bring standard as well as newer, cell-based and targeted therapies to our patients and cover the costs of highly effective therapies. I also remain hopeful that improving technological capabilities and payment reforms will be used by innovative clinical and administrative care teams to give clinicians more time to improve the care and health of patients while validating the methodologies so that real world data can help us further craft therapies to improve the health of each individual who needs our care. As we close this 15th year of our journal, we hope our presentations of practical science and implementation content has helped support your work while freeing some time for you to enjoy the journey. Our best wishes for a joyful holiday season celebrated with friends and family and the patients who entrust us to help them face and live beyond their cancer diagnoses.

This past year will likely be remembered as one of breakthrough advances in reducing the burden of cancer, with some landmark “firsts” coming out of the US Food and Drug Administration (FDA). Among the notable approvals were the first CART [chimeric antigen receptor T-cell] immunotherapies – tisagenlecleucel (Kymriah) for B-cell precursor acute lymphoblastic leukemia, and axicabtagene ciloleucel (Yescarta) for relapsed or refractory large B-cell lymphoma; the first US-approved biosimilar for cancer, bevacizumab-awwb (Mvasi) for multiple types of cancer; and first-time approvals for neratinib (Nerlynx) as an extended adjuvant therapy for early-stage human epidermal growth factor receptor 2 (HER2)-overexpressed/amplified breast cancer, and avelumab (Bavencio) for the treatment of metastatic Merkel cell carcinoma. But our excitement about those advances will undoubtedly be tempered by the continued challenges in expanding access to better quality health care, piloting more effective payment models, and consolidating delivery systems.

Our excitement has also been tempered by the rapid rise in the cost of effective biologic, immunologic, and targeted therapies. With the approval of trastuzumab-dkst (Ogivri), the first targeted biosimilar for HER2-positive breast and gastrointestinal cancers, we can look forward to price decreases possibly in the 20%-30% range over time from a targeted therapy with remarkable clinical efficacy. We know that approved biosimilars have demonstrated clinical efficacy along with similar minor biologic diversity that is also seen in the reference biologic.¹ We can also hope that increasing competition among biosimilar and reference compounds will lead to improvements in production methodologies that can allow further price reductions so that even more patients can gain access to these highly effective therapies.

In addition, the first FDA approval for the next-generation sequencing (NGS) FoundationOne profiling test and the rapid announcement by the Centers for Medicare & Medicaid Services (CMS) that it will cover the cost of that testing brings us a step closer to knowing which patients most likely will or won’t benefit from costly and toxic targeted therapies. Along with the many clinical trials studying which mutations predict which efficacies of individual or combinations of targeted agents, the approval and CMS coverage policy will help us improve value to our patients; when we can recommend the most beneficial therapies and avoid futile ones.

Finally, the approval for the DigniCap Scalp Cooling System for patients on chemotherapy for all solid tumors is of great importance. Pending coverage availability, it may influence some patients to get chemotherapy they might otherwise have forgone to avoid hair loss (see related article).

More consolidation: the best of all worlds?

In my 27 years in private practice, during which practice revenues grew with the favorable profit margins on novel therapies, forward-thinking physician leaders piloted innovations in oncology electronic medical records (EMRs), the delivery of team-based care, clinical research partnerships, and more comprehensive care services to better serve diverse communities, including those in rural areas. At my previous practice, that included adding clinicians to our group to serve patients at hospital clinics in 2 counties in southern California, each county with populations larger than 15 states. Our private practice worked with these public entities to bring state-of-the art care and private practice efficiencies to the uninsured and underserved in our region.

Unfortunately, revenues plummeted with changes in reimbursement after passage of the Medicare Modernization Act in 2003 and they continue to destabilize and reduce the number of community practices across the country. Many oncologists and oncology practices, including mine, chose to join larger academic or hospital systems or larger oncology networks at a time they are also facing growing pressures to contain costs, focus on out-patient care, complex clinical trials, and expanded access to care.

Although we may lament the shrinking landscape of private oncology practices, we can also be inspired by the physicians who have joined ranks with the better-funded, better-resourced, more traditional hospital and academic systems. These larger systems have more resources, more clincial trial offerings, staffing, technology, and analytics to expand value-based care initiatives to larger numbers of patients.

The hub-and-spoke models of oncology care with integrated networks linked by technology, and networked into larger analytic and decision support systems such as CancerLinQ, the health information technology program of the American Society of Clinical Oncology (ASCO),² could facilitate documentable delivery of comprehensive, evidence-based care, moving us closer to meeting the Quadruple Aim of optimal health care: improving the patient experience of care (including quality and satisfaction); improving the health of populations; reducing the per capita cost of health care; and improving the work life of those who deliver care.^3,4

Payment reform: working to align incentives

Everyone seems to agree that the fee-for-service payment models do not align incentives for improving total health outcomes at the lowest costs, but at the moment, there seems to be no best way of aligning them. Robinson has reported on the oncology payment initiatives at four major health insurance plans – Medicare (public) and Anthem, Aetna, and UnitedHealthcare (all private), noting that:⁵

• Medicare is testing its Oncology Care Model at more than 200 sites in the United States, and early data are expected to be released in 2018.
• Anthem continues with its Cancer Care Quality Program that includes adherence to 2 key requirements: that participants are compliant with Anthem-approved drug pathways, and that they register their patients at the insurer’s oncology website and enter their clinical data. Anthem is also considering expanding the management fee for certain high priority clinical trials.
• Aetna’s Oncology Solutions takes a different approach by providing increased payments for generic chemotherapies.
• United has eliminated the mark-up for new drugs and continues to mark up the prices of the older and generic therapies. Its episode-based pricing gives practices upfront payments based on expected drug margins so that practices can fund more comprehensive evidence-based care. In a presentation at a Washington State Medical Oncology Society meeting recently, United’s Lee Newcomer, reported that the insurer continues to see improved clinical and financial outcomes as well as encouraging early data showing that patients might do better in the real-world setting on some therapies that have not been fully compared in head-to-head randomized clinical trials.^6,7

ASCO is pulling these ideas together at the national level with its Patient-Centered Oncology Payment (PCOP) model, which is similar to Medicare’s alternative payment model. The PCOP model focuses on high-value, quality care. Higher upfront payments would cover the additional diagnostic services, care planning, and management to improve compliance and adherence as well as clinical trial evaluations. The model was developed and vetted by the ASCO Clinical Practice Committee and practicing oncologists, and is supported by staff and consultants. It is currently in its second year of operation with a commercial payer and will be submitted for review to the Physician-Focused Payment Model Technical Advisory Committee of the Health and Human Services. The results of the review are expected in 2018. If the model is approved, it could provide a uniform approach for payers that would align incentives for high-quality cancer care and allow for better predictive modeling for practices, irrespective of size, to invest in infrastructure and staffing to meet the growing demand for high-quality, value-based cancer care.

Better science: the promise of more cures

The FDA approved a record number drugs and biologics in 2017 for various cancers,⁸ including the landmark approval of the first CART therapy for cancer, tisagenlecleucel, which targets CD19 on B cells in the treatment of acute leukemia. That approval was rapidly followed by a second anti-CD19 CART therapy, axicabtagene ciloluecel, for refractory, aggressive B-cell non-Hodgkin lymphoma.^9,10 Although these therapies can achieve remarkable response and even complete response rates in otherwise refractory patients, only some achieve a long-term remission, and the costs are an order of magnitude above most other cancer therapies. That raises the question of what duration of benefit we should expect for treatments that cost in the range of $500,000 for the therapy alone, along with the additional costs for care, hospitalization, monitoring, expensive biologics (eg, tocilizumab, for the severe and potentially life-threatening cytokine-release syndrome associated with CART therapies), and significant neurologic and other therapy-related toxicities.

Novel arrangements between pharmaceutical companies and payers are currently being discussed so that only patients who meet specific response criteria would be charged for the therapy. In addition, we await findings from ongoing research to see if new approaches can find specific targetable sites on solid tumors that could spare the healthy organ tissues while eliminating highly resistant or heterogeneous populations of mutations in patients with advanced solid tumors. Such development of highly specific targets for CART therapies would improve their efficacy and safety, and with defined protocols in place to address toxicities and efforts to reduce the costs of the therapies, we can hopefully ensure broader access for patients to this potentially transformative therapeutic tool.

In addition to the excitement around the CART therapies, many of the years other new approvals will bring incremental but meaningful improvement in outcomes for patients with common cancers. The approval of neratinib, the first agent approved as extended adjuvant therapy for women with early-stage HER2/neu-positive breast cancer, is welcome, given the current 30% recurrence risk that extends past 10 years for women in that disease population who have completed standard adjuvant HER2-directed therapies. The 34% reduction in recurrence risk with a year of extended oral adjuvant therapy, as reported by Martin and colleagues,¹¹ with benefits sustained out to 5 years and with controllable diarrhea as the major toxicity, are encouraging. This oral therapy may be especially beneficial for hormone-receptor–positive women in whom blocking the HER2/neu pathway may enhance cell signaling through the hormone pathways, which can be blocked with oral agents at the same time to provide significant reduction of recurrence risk.

Diagnostics

The concept of personalized medicine is based on identifying biomarkers that are predictive of a patient’s response to treatment. There has been much progress toward applying NGS of tumors for use in the clinic, but we are still awaiting evidence from randomized clinical trials that such approaches prolong overall or progression-free survival.¹² Dr Julie Lange, an associate professor of clinical surgery and director of the Breast Cancer Program at the Keck School of Medicine at the University of Southern California, Los Angeles, provided me with the references to key studies in this field in which she is a leading researcher.¹³ However, she pointed out that in the absence of effective therapies, advanced biomarker testing may be less helpful, as is the case in heavily pretreated patients,¹⁴ unless a molecular test can pinpoint a potentially clinically actionable mutation. With the plethora of available assays and the high costs of molecular testing, clinicians are challenged in knowing what testing is best for which patients. Findings from a number of key ongoing national trials may eventually help us understand which tumor mutations in which tumor types can be most effectively targeted when multiple targetable mutations are found (TAPUR,¹⁵ MATCH,¹⁶ and QUILT¹⁷ and other basket trials¹⁸). The complexity of molecular testing has led to the development of institutional, trial-based, or co-operative group molecular tumor boards to provide guidance on specific targeted therapies for specific tumor mutations.

ASCO has launched a monthly series called Molecular Oncology Tumor Boards¹⁹ to expand the knowledge base in this field. It is presented as user-driven discussions designed to help providers integrate the use of the new genetic and genomic tests and their results into the day-to-day clinical care of patients with cancer.²⁰

Liquid biopsies

As busy clinicians, we need to understand the differences in liquid biopsy tests and their correlation with actionable targets, especially given the rapid progress in this field. Again, Dr Lange offered clarity on those differences. Liquid biopsy, refers to using a blood draw to isolate circulating tumor cells (CTCs) or circulating tumor DNA (ctDNA) to assess tumor biomarkers.²¹ Both CTCs and ctDNA tests have been shown to be prognostic of worse survival.^22-24 Liquid biopsies are currently supplemental to direct tumor biopsies, not replacements for them. The theoretical advantage of liquid biopsies is that they may reflect tumor heterogeneity by examining the repertoire of mutations contributed by diverse metastatic sites that shed CTCs or ctDNA into the circulation. The question is which type of testing can best inform therapy decisions.

Assays for ctDNA using droplet digital PCR [polymerase chain reaction], a digital PCR method based on water-oil emulsion droplet technology, require a priori knowledge of the specific mutation associated with response or lack of response to a specific therapy.^25,26 Technical issues related to the detection of rare alleles present within a mixed population of leukocytes, and ctDNA remains a challenge for many ctDNA assays. However, there is evidence to suggest that whole-exome sequencing of ctDNA is concordant with mutations in metastases,²⁷ however benchmarking ctDNA against tissue biopsies of metastases was not possible in all studies because tumor blocks were not available or because of the failure of tumor NGS assays. ^28,29

Newer generations of CTC assays take advantage of the circulating tumor cell as a functional assay for mutational status, gene expression, proteomics, epigenetics, and/or chemosensitivity of cultured cells. The relationship between CTCs and ctDNA remains uncertain as to whether CTCs are the cell of origin for ctDNA or if ctDNA may reflect responding or resistant tumor populations. The use of NGS on tumor specimens, ctDNA, and CTCs as a discovery tool is advancing the field by improving the understanding of disease heterogeneity and potential treatment targets. These results require correlation with patterns of response to therapy, and ultimately require validation in randomized clinical trials to provide strong evidence justifying their use outside of clinical trials. We can look forward to a time in the not distant future when specific liquid biopsy assays will reflect the array of mutations in different metastatic sites with validation that they correlate with efficacy of targeting those mutations that have targetable therapies.

From the FDA

New approvals

• Trastuzumab-dkst (Ogivri, Mylan; Dec 1) was approved as a biosimilar to trastuzumab (Herceptin, Genentech) for the treatment of patients with HER2-overexpressing breast or metastatic stomach cancer (gastric or gastroesophageal junction adenocarcinoma).
• Sunitinib malate (Sutent, Pfizer; Nov 16) was approved for the adjuvant treatment of adult patients at high risk of recurrent renal cell carcinoma after nephrectomy.
• Obinutuzumab (Gazyva, Genentech; Nov 16) received regular approval in combination with chemotherapy, followed by obinutuzumab monotherapy in patients achieving partial remission, for adult patients with previously untreated stage II bulky, III, or IV follicular lymphoma.
• Emicizumab-kxwh (Hemlibra, Genentech; Nov 16) was approved for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A with factor VIII inhibitors.
• Dasatinib (Sprycel, Bristol-Myers Squibb; Nov 9) was approved for the treatment of pediatric patients with Philadelphia chromosome-positive chronic myeloid leukemia (CML) in the chronic phase.
• Brentuximab vedotin (Adcetris, Seattle Genetics; Nov 9) for the treatment of previously treated adult patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides.
• Alectinib (Alecensa, Hoffmann-La Roche/Genentech; Nov 6) was approved for treatment of patients with anaplastic lymphoma kinase–positive metastatic non-small cell lung cancer (NSCLC), as detected by an FDA-approved test.
• Vemurafenib (Zelboraf, Hoffmann-La Roche; Nov 6) received approval for the treatment of Acalabrutinib (Calquence, AstraZeneca/Acerta; Oct 31) was granted accelerated approval for treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one previous therapy.
• Axicabtagene ciloleucel (Yescarta, Kite; Oct 18), a CART therapy, was approved for treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. The complete remission rate reviewed by the FDA for trial patients was 51%.³⁰ It was the second CART therapy this year to receive approval (see tisagenlecleucel; Aug 30). The agency granted orphan drug designation and priority review to therapy for this indication.
• Abemaciclib (Verzenio, Eli Lilly; Sep 28) was approved in combination with fulvestrant for women with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy.
• Copanlisib (Aliqopa, Bayer; Sep 14) got accelerated approval for the treatment of adult patients with relapsed follicular lymphoma who have received at least two prior systemic therapies.
• Bevacizumab-awwb (Mvasi, Amgen; Sep 14) was approved as a biosimilar to bevacizumab (Avastin, Genentech) for treating multiple types of cancer. It was the first biosimilar approved in the US for the treatment of cancer.
• Gemtuzumab ozogamicin (Mylotarg, Pfizer; Sep 1) was approved for the treatment of newly diagnosed CD33-positive acute myeloid leukemia (AML) in adults and of relapsed/refractory CD33-positive AML in adults and pediatric patients aged 2 or older. It can be used in combination with daunorubicin and cytarabine for adults with newly diagnosed AML, or as a standalone treatment for certain adult and pediatric patients. The drug was originally approved in 2000 as a standalone treatment for CD33-positive AML in patients older than 60 years, but was withdrawn in 2010 because of safety concerns and postmarketing trials could not confirm benefit. The current approval is for a lower recommended dose and schedule.³¹
• Tisagenlecleucel (Kymriah, Novartis; Aug 30) was approved for the treatment of patients up to age 25 years with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. It is the first CART immunotherapy approved by the agency.
• Inotuzumab ozogamicin (Besponsa, Wyeth; Aug 17) was approved for the treatment of adults with relapsed or refractory B-cell precursor ALL.
• A liposome-encapsulated combination of daunorubicin and cytarabine (Vyxeos, Jazz; Aug 3) was approved for the treatment of adults with newly diagnosed therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC), two types of AML having a poor prognosis.
• Enasidenib (Idhifa, Celgene; Aug 1) was approved for the treatment of adult patients with relapsed or refractory AML with an isocitrate dehydrogenase-2 mutation as detected by an FDA-approved test.
• Neratinib (Nerlynx, Puma; Jul 17) was approved as the first extended adjuvant therapy for adult patients with early stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy.
• Blinatumomab (Blincyto, Amgen; Jul 11) was approved for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia in adults and children.
• L-glutamine oral powder (Endari, Emmaus; Jul 7) was approved for oral administration to reduce the acute complications of sickle cell disease in adult and pediatric patients 5 years and older.
• Betrixaban (Bevyxxa, Portola; Jun 23) was approved for the prophylaxis of venous thromboembolism (VTE) in adult patients hospitalized for an acute medical illness who are at risk for thromboembolic complications because of moderate or severe restricted mobility and other risk factors for VTE.
• The combination of rituximab and hyaluronidase human (Rituxan Hycela, Genentech; Jun 22) was approved for adult patients with follicular lymphoma, DLBCL, and chronic lymphocytic leukemia. Hyaluronidase human is an enzyme that helps deliver the rituximab. This formulation allows subcutaneous administration of the combination, which will shorten patient visit times and potentially even allow at-home therapy delivery.
• Ceritinib (Zykadia, Novartis; May 26) was approved for patients with metastatic NSCLC whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.
• Avelumab (Bavencio, EMD Serono; May 9) got accelerated approval for patients with locally advanced or metastatic urothelial carcinoma whose disease progressed during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.
• Durvalumab (ImfinzI, AstraZeneca; May 1) got accelerated approval for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
• Brigatinib (Alunbrig tablets, Takeda through Ariad; Apr 28) got accelerated approval for the treatment of patients with metastatic anaplastic lymphoma kinase (ALK)-positive NSCLC who have progressed on or are intolerant to crizotinib.
• Midostaurin (Rydapt, Novartis; Apr 28) was approved for the treatment of adult patients with newly diagnosed AML who are FLT3 mutation-positive, as detected by an FDA-approved test, in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation.
• Osimertinib (Tagrisso, AstraZeneca; Mar 30) got regular approval for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive NSCLC, as detected by an FDA-approved test, whose disease has progressed on or after EGFR tyrosine-kinase inhibitor therapy.
• Niraparib (Zejula, Tesaro; Mar 27), a poly ADP-ribose polymerase (PARP) inhibitor, was approved for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy.
• Avelumab (Mar 23), a PD-L1–blocking human IgG1 lambda monoclonal antibody, got accelerated approval for the treatment of patients 12 years and older with metastatic Merkel cell carcinoma. It is the first FDA-approved product to treat this type of cancer.
• Ribociclib (Kisqali, Novartis; Mar 13), a CDK4/6 inhibitor, was approved as a breakthrough therapy after priority review for use in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer.

Expanded/additional indications

• Nivolumab (Opdivo, Bristol-Myers Squibb; Sep 22) got accelerated expanded indication approval for treatment of hepatocellular carcinoma (HCC) in patients previously treated with sorafenib.
• Pembrolizumab (Keytruda, Merck; Sep 22) got accelerated expanded indication approval for recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma in patients whose tumors express PD-L1 as determined by an FDA-approved test.
• DigniCap Scalp Cooling System (Dignitana Inc; Jul 3) was cleared for expanded use for reducing hair loss during chemotherapy for all solid tumors. Marketing authorization for the cooling cap had been granted in 2015 for patients with breast cancer.
• Olaparib tablets (Lynparza, AstraZeneca; Aug 17) got approval for an expanded indication as maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in a complete or partial response to platinum-based chemotherapy.
• Ibrutinib (Imbruvica, Pharmacyclics; Aug 2) got expanded indication approval for the treatment of adult patients with chronic graft-versus-host disease (cGVHD) after failure of one or more lines of systemic therapy. It was the first FDA-approved therapy for the treatment of cGVHD. (Ibrutinib was previously approved for chronic lymphocytic leukemia/small lymphocytic lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma with 17p deletion, Waldenström’s macroglobulinemia, marginal zone lymphoma, and mantle cell lymphoma).
• Nivolumab (Aug 2) got an accelerated expanded indication for the treatment of patients 12 years and older with mismatch repair deficient (dMMR) and microsatellite instability-high (MSI-H) metastatic colorectal cancer that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
• Dabrafenib and trametinib (Tafinlar and Mekinist, Novartis; Jun 22) were approved for the expanded indication in combination for patients with metastatic NSCLC with BRAF V600E mutation as detected by an FDA-approved test. The combination demonstrated superior efficacy compared with dabrafenib alone (overall response rate: 61% and 27%, respectively).³²
• Pembrolizumab (May 23) got approved for expanded indication for adult and pediatric patients with unresectable or metastatic, MSI-H or dMMR solid tumors that have progressed after treatment and who have no satisfactory alternative treatment options or with MSI-H or dMMR colorectal cancer that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
• Pembrolizumab (May 18) got approval for expanded indication for patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
• Pembrolizumab (May 10) got accelerated expanded indication for use combination with pemetrexed and carboplatin for the treatment of patients with previously untreated metastatic NSCLC.
• Regorafenib (Stivarga, Bayer; Apr 27) got an additional indication for the treatment of patients with HCC who have been previously treated with sorafenib.
• Palbociclib (Ibrance, Pfizer; Mar 31) got an expanded indication that includes first-line therapy for the treatment of hormone receptor–positive, HER2-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine based therapy in postmenopausal women.
• Pembrolizumab (Mar 15) got an accelerated additional indication approval for treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma, or those who have relapsed after three or more previous lines of therapy.
• Lenalidomide (Revlimid, Celgene; Feb 22) got an additional indication as maintenance therapy for patients with multiple myeloma following autologous stem cell transplant.
• Nivolumab (Feb 2) got an accelerated expanded indication for treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with a platinum-containing chemotherapy.

Modified use

• Cabazitaxel (Jevtana, Sanofi-Aventis; Sep 14) in combination with prednisone was approved at a lower dose of 20 mg/m² every 3 weeks for the treatment of patients with metastatic castration-resistant prostate cancer previously treated with a docetaxel-containing treatment regimen. It had been approved at 25 mg/m² every 3 weeks for this indication in 2010.

Tests/diagnostics

• Marketing approval was given to the FoundationOne CDx (Foundation Medicine; Nov 30), an NGS-based in vitro diagnostic to detect genetic mutations in 324 genes and 2 genomic signatures in any solid tumor type.
• Marketing approval was given to the Praxis Extended RAS Panel (Illumina; Jun 29), a next generation sequencing test to detect certain genetic mutations in RAS genes in tumor samples of patients with metastatic colorectal cancer. The test is used to aid in the identification of patients who may be eligible for treatment with panitumumab (Vectibix, Amgen).
• Marketing was approved for ipsogen JAK2 RGQ PCR Kit (Qiagen ; Mar 27) to detect mutations affecting the Janus tyrosine kinase 2 gene. This is the first FDA-authorized test intended to help physicians in evaluating patients for suspected polycythemia vera.

Imaging and pathology aids

• Aminolevulinic acid hydrochloride, known as ALA HCl (Gleolan, NX; Jun 6) was approved as an optical imaging agent indicated in patients with gliomas (suspected World Health Organization grades III or IV on preoperative imaging) as an adjunct for the visualization of malignant tissue during surgery.
• Marketing was approved for the Philips IntelliSite Pathology Solution (PIPS, Philips Medical Systems Nederland; Apr 17), as an aid to the pathologist to review and interpret digital images of surgical pathology slides prepared from formalin-fixed paraffin embedded tissue.
   

Challenges and uncertainties

The current administration’s initiatives to reduce administrative burdens is underway with the Patients Over Paperwork initiative. Eliminating and streamlining regulations to increase efficiency and improve beneficiary experience could be helpful to both oncologists and patients. For now, the Medicare Access and CHIP Reauthorization Act (MACRA) program, allows you to “pick your pace” in the 2017 performance year and report on at least one measure to avoid a payment reduction penalty on your Medicare payments in 2019. In the final rule for 2018, the CMS finalized a proposal to apply the MIPS [Merit-based Incentive Payment System] adjustment to all Part B items and services, which will include Part B drugs. This would be unfair to oncologists who treat on the basis of evidence-based guidelines and pathways and have no control over the costs of the drugs they prescribe.

In addition, more requirements will be imposed in 2018 in a move toward full MACRA implementation. All four composite categories (Quality – 60% for 2017; Advancing Care Information (ACI, renamed from Meaningful Use) – 25% for 2017; Improvement Activities (IA) – 15% for 2017; and Cost – 0% for 2017, but weighted in the future) will be scored, including resource use (cost) at 10%. CMS will collect data to assess the total cost of care and the Medicare Spend per Beneficiary to assess use. Full program implementation, with cost being assessed at 30% of your score is expected in the 2019 performance year. ASCO’s clinical affairs and policy experts have studied the implications of Part B chemotherapy drugs being included in the cost component of the MIPS scoring and will continue advocating for policies that hold clinicians responsible only for the aspects of care they can control, such as providing high-quality care based on the patient’s disease, biomarkers, comorbidities, and preferences, and not the costs of the evidence-based therapies needed by patients.
 

Toward a better 2018 for ourselves and our patients

As an eternal optimist, I remain enthusiastic that despite the many challenges, we will find effective ways to bring standard as well as newer, cell-based and targeted therapies to our patients and cover the costs of highly effective therapies. I also remain hopeful that improving technological capabilities and payment reforms will be used by innovative clinical and administrative care teams to give clinicians more time to improve the care and health of patients while validating the methodologies so that real world data can help us further craft therapies to improve the health of each individual who needs our care. As we close this 15th year of our journal, we hope our presentations of practical science and implementation content has helped support your work while freeing some time for you to enjoy the journey. Our best wishes for a joyful holiday season celebrated with friends and family and the patients who entrust us to help them face and live beyond their cancer diagnoses.

This past year will likely be remembered as one of breakthrough advances in reducing the burden of cancer, with some landmark “firsts” coming out of the US Food and Drug Administration (FDA). Among the notable approvals were the first CART [chimeric antigen receptor T-cell] immunotherapies – tisagenlecleucel (Kymriah) for B-cell precursor acute lymphoblastic leukemia, and axicabtagene ciloleucel (Yescarta) for relapsed or refractory large B-cell lymphoma; the first US-approved biosimilar for cancer, bevacizumab-awwb (Mvasi) for multiple types of cancer; and first-time approvals for neratinib (Nerlynx) as an extended adjuvant therapy for early-stage human epidermal growth factor receptor 2 (HER2)-overexpressed/amplified breast cancer, and avelumab (Bavencio) for the treatment of metastatic Merkel cell carcinoma. But our excitement about those advances will undoubtedly be tempered by the continued challenges in expanding access to better quality health care, piloting more effective payment models, and consolidating delivery systems.

Our excitement has also been tempered by the rapid rise in the cost of effective biologic, immunologic, and targeted therapies. With the approval of trastuzumab-dkst (Ogivri), the first targeted biosimilar for HER2-positive breast and gastrointestinal cancers, we can look forward to price decreases possibly in the 20%-30% range over time from a targeted therapy with remarkable clinical efficacy. We know that approved biosimilars have demonstrated clinical efficacy along with similar minor biologic diversity that is also seen in the reference biologic.¹ We can also hope that increasing competition among biosimilar and reference compounds will lead to improvements in production methodologies that can allow further price reductions so that even more patients can gain access to these highly effective therapies.

In addition, the first FDA approval for the next-generation sequencing (NGS) FoundationOne profiling test and the rapid announcement by the Centers for Medicare & Medicaid Services (CMS) that it will cover the cost of that testing brings us a step closer to knowing which patients most likely will or won’t benefit from costly and toxic targeted therapies. Along with the many clinical trials studying which mutations predict which efficacies of individual or combinations of targeted agents, the approval and CMS coverage policy will help us improve value to our patients; when we can recommend the most beneficial therapies and avoid futile ones.

Finally, the approval for the DigniCap Scalp Cooling System for patients on chemotherapy for all solid tumors is of great importance. Pending coverage availability, it may influence some patients to get chemotherapy they might otherwise have forgone to avoid hair loss (see related article).

More consolidation: the best of all worlds?

In my 27 years in private practice, during which practice revenues grew with the favorable profit margins on novel therapies, forward-thinking physician leaders piloted innovations in oncology electronic medical records (EMRs), the delivery of team-based care, clinical research partnerships, and more comprehensive care services to better serve diverse communities, including those in rural areas. At my previous practice, that included adding clinicians to our group to serve patients at hospital clinics in 2 counties in southern California, each county with populations larger than 15 states. Our private practice worked with these public entities to bring state-of-the art care and private practice efficiencies to the uninsured and underserved in our region.

Unfortunately, revenues plummeted with changes in reimbursement after passage of the Medicare Modernization Act in 2003 and they continue to destabilize and reduce the number of community practices across the country. Many oncologists and oncology practices, including mine, chose to join larger academic or hospital systems or larger oncology networks at a time they are also facing growing pressures to contain costs, focus on out-patient care, complex clinical trials, and expanded access to care.

Although we may lament the shrinking landscape of private oncology practices, we can also be inspired by the physicians who have joined ranks with the better-funded, better-resourced, more traditional hospital and academic systems. These larger systems have more resources, more clincial trial offerings, staffing, technology, and analytics to expand value-based care initiatives to larger numbers of patients.

The hub-and-spoke models of oncology care with integrated networks linked by technology, and networked into larger analytic and decision support systems such as CancerLinQ, the health information technology program of the American Society of Clinical Oncology (ASCO),² could facilitate documentable delivery of comprehensive, evidence-based care, moving us closer to meeting the Quadruple Aim of optimal health care: improving the patient experience of care (including quality and satisfaction); improving the health of populations; reducing the per capita cost of health care; and improving the work life of those who deliver care.^3,4

Payment reform: working to align incentives

Everyone seems to agree that the fee-for-service payment models do not align incentives for improving total health outcomes at the lowest costs, but at the moment, there seems to be no best way of aligning them. Robinson has reported on the oncology payment initiatives at four major health insurance plans – Medicare (public) and Anthem, Aetna, and UnitedHealthcare (all private), noting that:⁵

• Medicare is testing its Oncology Care Model at more than 200 sites in the United States, and early data are expected to be released in 2018.
• Anthem continues with its Cancer Care Quality Program that includes adherence to 2 key requirements: that participants are compliant with Anthem-approved drug pathways, and that they register their patients at the insurer’s oncology website and enter their clinical data. Anthem is also considering expanding the management fee for certain high priority clinical trials.
• Aetna’s Oncology Solutions takes a different approach by providing increased payments for generic chemotherapies.
• United has eliminated the mark-up for new drugs and continues to mark up the prices of the older and generic therapies. Its episode-based pricing gives practices upfront payments based on expected drug margins so that practices can fund more comprehensive evidence-based care. In a presentation at a Washington State Medical Oncology Society meeting recently, United’s Lee Newcomer, reported that the insurer continues to see improved clinical and financial outcomes as well as encouraging early data showing that patients might do better in the real-world setting on some therapies that have not been fully compared in head-to-head randomized clinical trials.^6,7

ASCO is pulling these ideas together at the national level with its Patient-Centered Oncology Payment (PCOP) model, which is similar to Medicare’s alternative payment model. The PCOP model focuses on high-value, quality care. Higher upfront payments would cover the additional diagnostic services, care planning, and management to improve compliance and adherence as well as clinical trial evaluations. The model was developed and vetted by the ASCO Clinical Practice Committee and practicing oncologists, and is supported by staff and consultants. It is currently in its second year of operation with a commercial payer and will be submitted for review to the Physician-Focused Payment Model Technical Advisory Committee of the Health and Human Services. The results of the review are expected in 2018. If the model is approved, it could provide a uniform approach for payers that would align incentives for high-quality cancer care and allow for better predictive modeling for practices, irrespective of size, to invest in infrastructure and staffing to meet the growing demand for high-quality, value-based cancer care.

Better science: the promise of more cures

The FDA approved a record number drugs and biologics in 2017 for various cancers,⁸ including the landmark approval of the first CART therapy for cancer, tisagenlecleucel, which targets CD19 on B cells in the treatment of acute leukemia. That approval was rapidly followed by a second anti-CD19 CART therapy, axicabtagene ciloluecel, for refractory, aggressive B-cell non-Hodgkin lymphoma.^9,10 Although these therapies can achieve remarkable response and even complete response rates in otherwise refractory patients, only some achieve a long-term remission, and the costs are an order of magnitude above most other cancer therapies. That raises the question of what duration of benefit we should expect for treatments that cost in the range of $500,000 for the therapy alone, along with the additional costs for care, hospitalization, monitoring, expensive biologics (eg, tocilizumab, for the severe and potentially life-threatening cytokine-release syndrome associated with CART therapies), and significant neurologic and other therapy-related toxicities.

Novel arrangements between pharmaceutical companies and payers are currently being discussed so that only patients who meet specific response criteria would be charged for the therapy. In addition, we await findings from ongoing research to see if new approaches can find specific targetable sites on solid tumors that could spare the healthy organ tissues while eliminating highly resistant or heterogeneous populations of mutations in patients with advanced solid tumors. Such development of highly specific targets for CART therapies would improve their efficacy and safety, and with defined protocols in place to address toxicities and efforts to reduce the costs of the therapies, we can hopefully ensure broader access for patients to this potentially transformative therapeutic tool.

In addition to the excitement around the CART therapies, many of the years other new approvals will bring incremental but meaningful improvement in outcomes for patients with common cancers. The approval of neratinib, the first agent approved as extended adjuvant therapy for women with early-stage HER2/neu-positive breast cancer, is welcome, given the current 30% recurrence risk that extends past 10 years for women in that disease population who have completed standard adjuvant HER2-directed therapies. The 34% reduction in recurrence risk with a year of extended oral adjuvant therapy, as reported by Martin and colleagues,¹¹ with benefits sustained out to 5 years and with controllable diarrhea as the major toxicity, are encouraging. This oral therapy may be especially beneficial for hormone-receptor–positive women in whom blocking the HER2/neu pathway may enhance cell signaling through the hormone pathways, which can be blocked with oral agents at the same time to provide significant reduction of recurrence risk.

Diagnostics

The concept of personalized medicine is based on identifying biomarkers that are predictive of a patient’s response to treatment. There has been much progress toward applying NGS of tumors for use in the clinic, but we are still awaiting evidence from randomized clinical trials that such approaches prolong overall or progression-free survival.¹² Dr Julie Lange, an associate professor of clinical surgery and director of the Breast Cancer Program at the Keck School of Medicine at the University of Southern California, Los Angeles, provided me with the references to key studies in this field in which she is a leading researcher.¹³ However, she pointed out that in the absence of effective therapies, advanced biomarker testing may be less helpful, as is the case in heavily pretreated patients,¹⁴ unless a molecular test can pinpoint a potentially clinically actionable mutation. With the plethora of available assays and the high costs of molecular testing, clinicians are challenged in knowing what testing is best for which patients. Findings from a number of key ongoing national trials may eventually help us understand which tumor mutations in which tumor types can be most effectively targeted when multiple targetable mutations are found (TAPUR,¹⁵ MATCH,¹⁶ and QUILT¹⁷ and other basket trials¹⁸). The complexity of molecular testing has led to the development of institutional, trial-based, or co-operative group molecular tumor boards to provide guidance on specific targeted therapies for specific tumor mutations.

ASCO has launched a monthly series called Molecular Oncology Tumor Boards¹⁹ to expand the knowledge base in this field. It is presented as user-driven discussions designed to help providers integrate the use of the new genetic and genomic tests and their results into the day-to-day clinical care of patients with cancer.²⁰

Liquid biopsies

As busy clinicians, we need to understand the differences in liquid biopsy tests and their correlation with actionable targets, especially given the rapid progress in this field. Again, Dr Lange offered clarity on those differences. Liquid biopsy, refers to using a blood draw to isolate circulating tumor cells (CTCs) or circulating tumor DNA (ctDNA) to assess tumor biomarkers.²¹ Both CTCs and ctDNA tests have been shown to be prognostic of worse survival.^22-24 Liquid biopsies are currently supplemental to direct tumor biopsies, not replacements for them. The theoretical advantage of liquid biopsies is that they may reflect tumor heterogeneity by examining the repertoire of mutations contributed by diverse metastatic sites that shed CTCs or ctDNA into the circulation. The question is which type of testing can best inform therapy decisions.

Assays for ctDNA using droplet digital PCR [polymerase chain reaction], a digital PCR method based on water-oil emulsion droplet technology, require a priori knowledge of the specific mutation associated with response or lack of response to a specific therapy.^25,26 Technical issues related to the detection of rare alleles present within a mixed population of leukocytes, and ctDNA remains a challenge for many ctDNA assays. However, there is evidence to suggest that whole-exome sequencing of ctDNA is concordant with mutations in metastases,²⁷ however benchmarking ctDNA against tissue biopsies of metastases was not possible in all studies because tumor blocks were not available or because of the failure of tumor NGS assays. ^28,29

Newer generations of CTC assays take advantage of the circulating tumor cell as a functional assay for mutational status, gene expression, proteomics, epigenetics, and/or chemosensitivity of cultured cells. The relationship between CTCs and ctDNA remains uncertain as to whether CTCs are the cell of origin for ctDNA or if ctDNA may reflect responding or resistant tumor populations. The use of NGS on tumor specimens, ctDNA, and CTCs as a discovery tool is advancing the field by improving the understanding of disease heterogeneity and potential treatment targets. These results require correlation with patterns of response to therapy, and ultimately require validation in randomized clinical trials to provide strong evidence justifying their use outside of clinical trials. We can look forward to a time in the not distant future when specific liquid biopsy assays will reflect the array of mutations in different metastatic sites with validation that they correlate with efficacy of targeting those mutations that have targetable therapies.

From the FDA

New approvals

• Trastuzumab-dkst (Ogivri, Mylan; Dec 1) was approved as a biosimilar to trastuzumab (Herceptin, Genentech) for the treatment of patients with HER2-overexpressing breast or metastatic stomach cancer (gastric or gastroesophageal junction adenocarcinoma).
• Sunitinib malate (Sutent, Pfizer; Nov 16) was approved for the adjuvant treatment of adult patients at high risk of recurrent renal cell carcinoma after nephrectomy.
• Obinutuzumab (Gazyva, Genentech; Nov 16) received regular approval in combination with chemotherapy, followed by obinutuzumab monotherapy in patients achieving partial remission, for adult patients with previously untreated stage II bulky, III, or IV follicular lymphoma.
• Emicizumab-kxwh (Hemlibra, Genentech; Nov 16) was approved for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A with factor VIII inhibitors.
• Dasatinib (Sprycel, Bristol-Myers Squibb; Nov 9) was approved for the treatment of pediatric patients with Philadelphia chromosome-positive chronic myeloid leukemia (CML) in the chronic phase.
• Brentuximab vedotin (Adcetris, Seattle Genetics; Nov 9) for the treatment of previously treated adult patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides.
• Alectinib (Alecensa, Hoffmann-La Roche/Genentech; Nov 6) was approved for treatment of patients with anaplastic lymphoma kinase–positive metastatic non-small cell lung cancer (NSCLC), as detected by an FDA-approved test.
• Vemurafenib (Zelboraf, Hoffmann-La Roche; Nov 6) received approval for the treatment of Acalabrutinib (Calquence, AstraZeneca/Acerta; Oct 31) was granted accelerated approval for treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one previous therapy.
• Axicabtagene ciloleucel (Yescarta, Kite; Oct 18), a CART therapy, was approved for treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. The complete remission rate reviewed by the FDA for trial patients was 51%.³⁰ It was the second CART therapy this year to receive approval (see tisagenlecleucel; Aug 30). The agency granted orphan drug designation and priority review to therapy for this indication.
• Abemaciclib (Verzenio, Eli Lilly; Sep 28) was approved in combination with fulvestrant for women with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy.
• Copanlisib (Aliqopa, Bayer; Sep 14) got accelerated approval for the treatment of adult patients with relapsed follicular lymphoma who have received at least two prior systemic therapies.
• Bevacizumab-awwb (Mvasi, Amgen; Sep 14) was approved as a biosimilar to bevacizumab (Avastin, Genentech) for treating multiple types of cancer. It was the first biosimilar approved in the US for the treatment of cancer.
• Gemtuzumab ozogamicin (Mylotarg, Pfizer; Sep 1) was approved for the treatment of newly diagnosed CD33-positive acute myeloid leukemia (AML) in adults and of relapsed/refractory CD33-positive AML in adults and pediatric patients aged 2 or older. It can be used in combination with daunorubicin and cytarabine for adults with newly diagnosed AML, or as a standalone treatment for certain adult and pediatric patients. The drug was originally approved in 2000 as a standalone treatment for CD33-positive AML in patients older than 60 years, but was withdrawn in 2010 because of safety concerns and postmarketing trials could not confirm benefit. The current approval is for a lower recommended dose and schedule.³¹
• Tisagenlecleucel (Kymriah, Novartis; Aug 30) was approved for the treatment of patients up to age 25 years with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. It is the first CART immunotherapy approved by the agency.
• Inotuzumab ozogamicin (Besponsa, Wyeth; Aug 17) was approved for the treatment of adults with relapsed or refractory B-cell precursor ALL.
• A liposome-encapsulated combination of daunorubicin and cytarabine (Vyxeos, Jazz; Aug 3) was approved for the treatment of adults with newly diagnosed therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC), two types of AML having a poor prognosis.
• Enasidenib (Idhifa, Celgene; Aug 1) was approved for the treatment of adult patients with relapsed or refractory AML with an isocitrate dehydrogenase-2 mutation as detected by an FDA-approved test.
• Neratinib (Nerlynx, Puma; Jul 17) was approved as the first extended adjuvant therapy for adult patients with early stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy.
• Blinatumomab (Blincyto, Amgen; Jul 11) was approved for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia in adults and children.
• L-glutamine oral powder (Endari, Emmaus; Jul 7) was approved for oral administration to reduce the acute complications of sickle cell disease in adult and pediatric patients 5 years and older.
• Betrixaban (Bevyxxa, Portola; Jun 23) was approved for the prophylaxis of venous thromboembolism (VTE) in adult patients hospitalized for an acute medical illness who are at risk for thromboembolic complications because of moderate or severe restricted mobility and other risk factors for VTE.
• The combination of rituximab and hyaluronidase human (Rituxan Hycela, Genentech; Jun 22) was approved for adult patients with follicular lymphoma, DLBCL, and chronic lymphocytic leukemia. Hyaluronidase human is an enzyme that helps deliver the rituximab. This formulation allows subcutaneous administration of the combination, which will shorten patient visit times and potentially even allow at-home therapy delivery.
• Ceritinib (Zykadia, Novartis; May 26) was approved for patients with metastatic NSCLC whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.
• Avelumab (Bavencio, EMD Serono; May 9) got accelerated approval for patients with locally advanced or metastatic urothelial carcinoma whose disease progressed during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.
• Durvalumab (ImfinzI, AstraZeneca; May 1) got accelerated approval for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
• Brigatinib (Alunbrig tablets, Takeda through Ariad; Apr 28) got accelerated approval for the treatment of patients with metastatic anaplastic lymphoma kinase (ALK)-positive NSCLC who have progressed on or are intolerant to crizotinib.
• Midostaurin (Rydapt, Novartis; Apr 28) was approved for the treatment of adult patients with newly diagnosed AML who are FLT3 mutation-positive, as detected by an FDA-approved test, in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation.
• Osimertinib (Tagrisso, AstraZeneca; Mar 30) got regular approval for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive NSCLC, as detected by an FDA-approved test, whose disease has progressed on or after EGFR tyrosine-kinase inhibitor therapy.
• Niraparib (Zejula, Tesaro; Mar 27), a poly ADP-ribose polymerase (PARP) inhibitor, was approved for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy.
• Avelumab (Mar 23), a PD-L1–blocking human IgG1 lambda monoclonal antibody, got accelerated approval for the treatment of patients 12 years and older with metastatic Merkel cell carcinoma. It is the first FDA-approved product to treat this type of cancer.
• Ribociclib (Kisqali, Novartis; Mar 13), a CDK4/6 inhibitor, was approved as a breakthrough therapy after priority review for use in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer.

Expanded/additional indications

• Nivolumab (Opdivo, Bristol-Myers Squibb; Sep 22) got accelerated expanded indication approval for treatment of hepatocellular carcinoma (HCC) in patients previously treated with sorafenib.
• Pembrolizumab (Keytruda, Merck; Sep 22) got accelerated expanded indication approval for recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma in patients whose tumors express PD-L1 as determined by an FDA-approved test.
• DigniCap Scalp Cooling System (Dignitana Inc; Jul 3) was cleared for expanded use for reducing hair loss during chemotherapy for all solid tumors. Marketing authorization for the cooling cap had been granted in 2015 for patients with breast cancer.
• Olaparib tablets (Lynparza, AstraZeneca; Aug 17) got approval for an expanded indication as maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in a complete or partial response to platinum-based chemotherapy.
• Ibrutinib (Imbruvica, Pharmacyclics; Aug 2) got expanded indication approval for the treatment of adult patients with chronic graft-versus-host disease (cGVHD) after failure of one or more lines of systemic therapy. It was the first FDA-approved therapy for the treatment of cGVHD. (Ibrutinib was previously approved for chronic lymphocytic leukemia/small lymphocytic lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma with 17p deletion, Waldenström’s macroglobulinemia, marginal zone lymphoma, and mantle cell lymphoma).
• Nivolumab (Aug 2) got an accelerated expanded indication for the treatment of patients 12 years and older with mismatch repair deficient (dMMR) and microsatellite instability-high (MSI-H) metastatic colorectal cancer that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
• Dabrafenib and trametinib (Tafinlar and Mekinist, Novartis; Jun 22) were approved for the expanded indication in combination for patients with metastatic NSCLC with BRAF V600E mutation as detected by an FDA-approved test. The combination demonstrated superior efficacy compared with dabrafenib alone (overall response rate: 61% and 27%, respectively).³²
• Pembrolizumab (May 23) got approved for expanded indication for adult and pediatric patients with unresectable or metastatic, MSI-H or dMMR solid tumors that have progressed after treatment and who have no satisfactory alternative treatment options or with MSI-H or dMMR colorectal cancer that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
• Pembrolizumab (May 18) got approval for expanded indication for patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
• Pembrolizumab (May 10) got accelerated expanded indication for use combination with pemetrexed and carboplatin for the treatment of patients with previously untreated metastatic NSCLC.
• Regorafenib (Stivarga, Bayer; Apr 27) got an additional indication for the treatment of patients with HCC who have been previously treated with sorafenib.
• Palbociclib (Ibrance, Pfizer; Mar 31) got an expanded indication that includes first-line therapy for the treatment of hormone receptor–positive, HER2-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine based therapy in postmenopausal women.
• Pembrolizumab (Mar 15) got an accelerated additional indication approval for treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma, or those who have relapsed after three or more previous lines of therapy.
• Lenalidomide (Revlimid, Celgene; Feb 22) got an additional indication as maintenance therapy for patients with multiple myeloma following autologous stem cell transplant.
• Nivolumab (Feb 2) got an accelerated expanded indication for treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with a platinum-containing chemotherapy.

Modified use

• Cabazitaxel (Jevtana, Sanofi-Aventis; Sep 14) in combination with prednisone was approved at a lower dose of 20 mg/m² every 3 weeks for the treatment of patients with metastatic castration-resistant prostate cancer previously treated with a docetaxel-containing treatment regimen. It had been approved at 25 mg/m² every 3 weeks for this indication in 2010.

Tests/diagnostics

• Marketing approval was given to the FoundationOne CDx (Foundation Medicine; Nov 30), an NGS-based in vitro diagnostic to detect genetic mutations in 324 genes and 2 genomic signatures in any solid tumor type.
• Marketing approval was given to the Praxis Extended RAS Panel (Illumina; Jun 29), a next generation sequencing test to detect certain genetic mutations in RAS genes in tumor samples of patients with metastatic colorectal cancer. The test is used to aid in the identification of patients who may be eligible for treatment with panitumumab (Vectibix, Amgen).
• Marketing was approved for ipsogen JAK2 RGQ PCR Kit (Qiagen ; Mar 27) to detect mutations affecting the Janus tyrosine kinase 2 gene. This is the first FDA-authorized test intended to help physicians in evaluating patients for suspected polycythemia vera.

Imaging and pathology aids

• Aminolevulinic acid hydrochloride, known as ALA HCl (Gleolan, NX; Jun 6) was approved as an optical imaging agent indicated in patients with gliomas (suspected World Health Organization grades III or IV on preoperative imaging) as an adjunct for the visualization of malignant tissue during surgery.
• Marketing was approved for the Philips IntelliSite Pathology Solution (PIPS, Philips Medical Systems Nederland; Apr 17), as an aid to the pathologist to review and interpret digital images of surgical pathology slides prepared from formalin-fixed paraffin embedded tissue.
   

Challenges and uncertainties

The current administration’s initiatives to reduce administrative burdens is underway with the Patients Over Paperwork initiative. Eliminating and streamlining regulations to increase efficiency and improve beneficiary experience could be helpful to both oncologists and patients. For now, the Medicare Access and CHIP Reauthorization Act (MACRA) program, allows you to “pick your pace” in the 2017 performance year and report on at least one measure to avoid a payment reduction penalty on your Medicare payments in 2019. In the final rule for 2018, the CMS finalized a proposal to apply the MIPS [Merit-based Incentive Payment System] adjustment to all Part B items and services, which will include Part B drugs. This would be unfair to oncologists who treat on the basis of evidence-based guidelines and pathways and have no control over the costs of the drugs they prescribe.

In addition, more requirements will be imposed in 2018 in a move toward full MACRA implementation. All four composite categories (Quality – 60% for 2017; Advancing Care Information (ACI, renamed from Meaningful Use) – 25% for 2017; Improvement Activities (IA) – 15% for 2017; and Cost – 0% for 2017, but weighted in the future) will be scored, including resource use (cost) at 10%. CMS will collect data to assess the total cost of care and the Medicare Spend per Beneficiary to assess use. Full program implementation, with cost being assessed at 30% of your score is expected in the 2019 performance year. ASCO’s clinical affairs and policy experts have studied the implications of Part B chemotherapy drugs being included in the cost component of the MIPS scoring and will continue advocating for policies that hold clinicians responsible only for the aspects of care they can control, such as providing high-quality care based on the patient’s disease, biomarkers, comorbidities, and preferences, and not the costs of the evidence-based therapies needed by patients.
 

Toward a better 2018 for ourselves and our patients

As an eternal optimist, I remain enthusiastic that despite the many challenges, we will find effective ways to bring standard as well as newer, cell-based and targeted therapies to our patients and cover the costs of highly effective therapies. I also remain hopeful that improving technological capabilities and payment reforms will be used by innovative clinical and administrative care teams to give clinicians more time to improve the care and health of patients while validating the methodologies so that real world data can help us further craft therapies to improve the health of each individual who needs our care. As we close this 15th year of our journal, we hope our presentations of practical science and implementation content has helped support your work while freeing some time for you to enjoy the journey. Our best wishes for a joyful holiday season celebrated with friends and family and the patients who entrust us to help them face and live beyond their cancer diagnoses.

From the Editor

Recent news events have detailed the many humiliations and abuses, both verbal and physical, that women, and some men, have to endure in the workforce. It would not surprise me if some vascular surgeons admit that they have heard of similar instances of egregious behavior occurring in our workplaces. The people that have been impacted have predominantly been women and have come from all walks of life. They have been patients, colleagues, our employees or those of the many institutions in which we work. Unfortunately, the demands of our profession and the pace of our lives may diminish our relationships with these persons. This facelessness and disconnection may allow some surgeons to justify their poor behavior whereas others may not realize that they are negatively impacting these individuals’ lives. The fact that these injustices persist is made more upsetting because we are so indebted for all that these nurses, technologists, office personnel, and even patients, do for us.

Just think how much we owe the nurses on the hospital floors. It is to nurses that we entrust the postoperative care of our patients. They make sure to call us when they detect that a pulse is weakening or suddenly absent, or that a neck is expanding as a hematoma threatens breathing. They timely diagnose a retroperitoneal bleed that may endanger the patient’s life. Dialysis nurses notify us that a puncture looks like it may suddenly bleed out. Our patients’ lives are often entirely dependent on the astute observation of an accomplished nurse.

And what about the operating nurses and scrub technicians? They lay out our surgical tray perfectly with all the tools that we are wont to use. They are there to assist when a sudden event requires the steady hand of an observant nurse who knows just what instrument we need without us having to ask. When you are in a difficult area, an encouraging word will often inspire the confidence required to accomplish a successful outcome. When a procedure is going poorly and tension mounts, their silence accepts our sometimes curt requests. There is a bond that develops between two professionals who recognize each other’s expertise.

Vascular technologists work tirelessly, often in darkened rooms, frequently under challenging positions straining eyes and limbs to detect pathology that may be life or limb saving. Their diagnostic acumen can be the difference between a subsequent procedure’s success or failure. Indeed, the vascular surgeon has to make the final interpretation, but if the technologist fails to show the pathology, even the most erudite physician may miss the diagnosis.

Front-desk personnel who sit at check-in and check-out in an office are the face of our practice. Their friendly attitude welcomes our patients and reassures them that they have come to a well-run, professional workplace. A smiling, personal greeting will calm even the most worried patient. Of course, their attention to detail assures that collections will not be misplaced.

Our office nurses exude compassion for the many patients who face immense hurdles in living with vascular disease. They assist in teaching wound care, explain medications, and help in arranging social services. They cry with those that have recently lost a spouse or child and get excited to hear of the birth of a patient’s grandchild. Without their organizational skills, office hours would be interminable, and patients who are kept waiting would complain, or worse, leave the practice. They have learned to laugh at the same joke that they have heard us tell innumerable times, and to ignore the sometimes lousy mood we may bring into the office after a brutal night on call.

The spouses or significant others of our patients also play an important role since it is often from them that we get the most accurate history. They will ask to speak to us privately to make sure we do not cause despair when we discuss treatment options or to ensure that we firmly admonish their loved one to stop smoking, exercise or watch their weight. Unfortunately, they will sometimes have to accept a disparaging remark or gesture from their “spouse” to make sure that we are supplied all the necessary information to come to an appropriate diagnosis.

I can go on about other medical personnel that contribute to our success, but I believe I have made the point. The men and women with whom we interact as vascular surgeons deserve the same respect we grant ourselves. Any insult to them demeans not only the recipient but more so the abuser and those of us who stand by silently.

Finally, there are many female colleagues whose interest and drive has allowed them to not only break into but achieve leadership positions in a specialty that was almost uniformly male and unwelcoming. Their aptitudes and attitudes have broadened the specialty’s ability to help our patients. However, recently the news has been replete with evidence that women have been abused as they tried to enter other male-dominated professions and so it is likely that this has happened in ours.

Other recent news items suggest that these physical and emotional abuses are inflicted not only on women but also men. We may never know the scope of this mistreatment, but we must assure that it stops immediately.

Ethical behavior must be gender neutral. Further, condescending attitudes, cruel language, and a lack of appreciation sometimes can be as damaging as physical or sexual abuse and must be abolished from our workplace. ■

From the Editor

Recent news events have detailed the many humiliations and abuses, both verbal and physical, that women, and some men, have to endure in the workforce. It would not surprise me if some vascular surgeons admit that they have heard of similar instances of egregious behavior occurring in our workplaces. The people that have been impacted have predominantly been women and have come from all walks of life. They have been patients, colleagues, our employees or those of the many institutions in which we work. Unfortunately, the demands of our profession and the pace of our lives may diminish our relationships with these persons. This facelessness and disconnection may allow some surgeons to justify their poor behavior whereas others may not realize that they are negatively impacting these individuals’ lives. The fact that these injustices persist is made more upsetting because we are so indebted for all that these nurses, technologists, office personnel, and even patients, do for us.

Just think how much we owe the nurses on the hospital floors. It is to nurses that we entrust the postoperative care of our patients. They make sure to call us when they detect that a pulse is weakening or suddenly absent, or that a neck is expanding as a hematoma threatens breathing. They timely diagnose a retroperitoneal bleed that may endanger the patient’s life. Dialysis nurses notify us that a puncture looks like it may suddenly bleed out. Our patients’ lives are often entirely dependent on the astute observation of an accomplished nurse.

And what about the operating nurses and scrub technicians? They lay out our surgical tray perfectly with all the tools that we are wont to use. They are there to assist when a sudden event requires the steady hand of an observant nurse who knows just what instrument we need without us having to ask. When you are in a difficult area, an encouraging word will often inspire the confidence required to accomplish a successful outcome. When a procedure is going poorly and tension mounts, their silence accepts our sometimes curt requests. There is a bond that develops between two professionals who recognize each other’s expertise.

Vascular technologists work tirelessly, often in darkened rooms, frequently under challenging positions straining eyes and limbs to detect pathology that may be life or limb saving. Their diagnostic acumen can be the difference between a subsequent procedure’s success or failure. Indeed, the vascular surgeon has to make the final interpretation, but if the technologist fails to show the pathology, even the most erudite physician may miss the diagnosis.

Front-desk personnel who sit at check-in and check-out in an office are the face of our practice. Their friendly attitude welcomes our patients and reassures them that they have come to a well-run, professional workplace. A smiling, personal greeting will calm even the most worried patient. Of course, their attention to detail assures that collections will not be misplaced.

Our office nurses exude compassion for the many patients who face immense hurdles in living with vascular disease. They assist in teaching wound care, explain medications, and help in arranging social services. They cry with those that have recently lost a spouse or child and get excited to hear of the birth of a patient’s grandchild. Without their organizational skills, office hours would be interminable, and patients who are kept waiting would complain, or worse, leave the practice. They have learned to laugh at the same joke that they have heard us tell innumerable times, and to ignore the sometimes lousy mood we may bring into the office after a brutal night on call.

The spouses or significant others of our patients also play an important role since it is often from them that we get the most accurate history. They will ask to speak to us privately to make sure we do not cause despair when we discuss treatment options or to ensure that we firmly admonish their loved one to stop smoking, exercise or watch their weight. Unfortunately, they will sometimes have to accept a disparaging remark or gesture from their “spouse” to make sure that we are supplied all the necessary information to come to an appropriate diagnosis.

I can go on about other medical personnel that contribute to our success, but I believe I have made the point. The men and women with whom we interact as vascular surgeons deserve the same respect we grant ourselves. Any insult to them demeans not only the recipient but more so the abuser and those of us who stand by silently.

Finally, there are many female colleagues whose interest and drive has allowed them to not only break into but achieve leadership positions in a specialty that was almost uniformly male and unwelcoming. Their aptitudes and attitudes have broadened the specialty’s ability to help our patients. However, recently the news has been replete with evidence that women have been abused as they tried to enter other male-dominated professions and so it is likely that this has happened in ours.

Other recent news items suggest that these physical and emotional abuses are inflicted not only on women but also men. We may never know the scope of this mistreatment, but we must assure that it stops immediately.

Ethical behavior must be gender neutral. Further, condescending attitudes, cruel language, and a lack of appreciation sometimes can be as damaging as physical or sexual abuse and must be abolished from our workplace. ■

From the Editor

Recent news events have detailed the many humiliations and abuses, both verbal and physical, that women, and some men, have to endure in the workforce. It would not surprise me if some vascular surgeons admit that they have heard of similar instances of egregious behavior occurring in our workplaces. The people that have been impacted have predominantly been women and have come from all walks of life. They have been patients, colleagues, our employees or those of the many institutions in which we work. Unfortunately, the demands of our profession and the pace of our lives may diminish our relationships with these persons. This facelessness and disconnection may allow some surgeons to justify their poor behavior whereas others may not realize that they are negatively impacting these individuals’ lives. The fact that these injustices persist is made more upsetting because we are so indebted for all that these nurses, technologists, office personnel, and even patients, do for us.

Just think how much we owe the nurses on the hospital floors. It is to nurses that we entrust the postoperative care of our patients. They make sure to call us when they detect that a pulse is weakening or suddenly absent, or that a neck is expanding as a hematoma threatens breathing. They timely diagnose a retroperitoneal bleed that may endanger the patient’s life. Dialysis nurses notify us that a puncture looks like it may suddenly bleed out. Our patients’ lives are often entirely dependent on the astute observation of an accomplished nurse.

And what about the operating nurses and scrub technicians? They lay out our surgical tray perfectly with all the tools that we are wont to use. They are there to assist when a sudden event requires the steady hand of an observant nurse who knows just what instrument we need without us having to ask. When you are in a difficult area, an encouraging word will often inspire the confidence required to accomplish a successful outcome. When a procedure is going poorly and tension mounts, their silence accepts our sometimes curt requests. There is a bond that develops between two professionals who recognize each other’s expertise.

Vascular technologists work tirelessly, often in darkened rooms, frequently under challenging positions straining eyes and limbs to detect pathology that may be life or limb saving. Their diagnostic acumen can be the difference between a subsequent procedure’s success or failure. Indeed, the vascular surgeon has to make the final interpretation, but if the technologist fails to show the pathology, even the most erudite physician may miss the diagnosis.

Front-desk personnel who sit at check-in and check-out in an office are the face of our practice. Their friendly attitude welcomes our patients and reassures them that they have come to a well-run, professional workplace. A smiling, personal greeting will calm even the most worried patient. Of course, their attention to detail assures that collections will not be misplaced.

Our office nurses exude compassion for the many patients who face immense hurdles in living with vascular disease. They assist in teaching wound care, explain medications, and help in arranging social services. They cry with those that have recently lost a spouse or child and get excited to hear of the birth of a patient’s grandchild. Without their organizational skills, office hours would be interminable, and patients who are kept waiting would complain, or worse, leave the practice. They have learned to laugh at the same joke that they have heard us tell innumerable times, and to ignore the sometimes lousy mood we may bring into the office after a brutal night on call.

The spouses or significant others of our patients also play an important role since it is often from them that we get the most accurate history. They will ask to speak to us privately to make sure we do not cause despair when we discuss treatment options or to ensure that we firmly admonish their loved one to stop smoking, exercise or watch their weight. Unfortunately, they will sometimes have to accept a disparaging remark or gesture from their “spouse” to make sure that we are supplied all the necessary information to come to an appropriate diagnosis.

I can go on about other medical personnel that contribute to our success, but I believe I have made the point. The men and women with whom we interact as vascular surgeons deserve the same respect we grant ourselves. Any insult to them demeans not only the recipient but more so the abuser and those of us who stand by silently.

Finally, there are many female colleagues whose interest and drive has allowed them to not only break into but achieve leadership positions in a specialty that was almost uniformly male and unwelcoming. Their aptitudes and attitudes have broadened the specialty’s ability to help our patients. However, recently the news has been replete with evidence that women have been abused as they tried to enter other male-dominated professions and so it is likely that this has happened in ours.

Other recent news items suggest that these physical and emotional abuses are inflicted not only on women but also men. We may never know the scope of this mistreatment, but we must assure that it stops immediately.

Ethical behavior must be gender neutral. Further, condescending attitudes, cruel language, and a lack of appreciation sometimes can be as damaging as physical or sexual abuse and must be abolished from our workplace. ■

Studies have shown that most of you already have deep-seated beliefs regarding guns. Some of you would frame the issue as Gun Rights, others as Gun Violence. I am not here to change your opinion. I am not in the habit of wasting my time. Logic has been drained from this discussion and emotion infused. As vascular surgeons, it is far past time to overcome these limitations and join the national discussion. Opinions and consensus statements have already been rendered from the American College of Surgeons, the American Medical Association, the American Academy of Pediatrics, the Society of Thoracic Surgeons, and even the American College of Phlebology. Where does the SVS stand?

In January 2013, the Board of Directors of the SVS voted to support the ACS Statement on Firearm Injuries. There is virtually no public record of this endorsement, it does not appear on the SVS website and it was essentially ignored by the public.

Even the diligent National Rifle Association (NRA) left the SVS off their list of “National Organizations with Anti-Gun Policies” (Ed note: for more information, see “The Evolution of the NRA and Our Modern Gun Debate” at www.vascularspecialistonline.com).

We need to do better. If we are truly an independent specialty it is time to behave as such. Vascular surgeons are on the front lines of this battle. We have cared for the injured, revived the dying, and bear witness to the dead. To not have a voice and be counted is a disservice to our patients and ourselves.

What can be done to reduce gun violence? In Australia, between 1979 and 1996, there were 13 mass shootings. After a semiautomatic weapon ban was instituted in 1996 there have been none. The U.S. ban on military style weapons lapsed in 2004. While it is difficult to characterize “mass shootings” in a country our size, there certainly seems to be an increase since then. If defined as “four or more shot and/or killed in a single event, at the same general time and location not including the shooter,” then we have seen 275 mass shootings this year as of Oct. 5, 2017.

The other statistics are familiar and sobering. More Americans have died from guns since 1968 than have died in all the wars since our country’s inception. The United States accounts for 91% of gun deaths of children among developed countries. Our casualty figures more closely mirror Somalia and Honduras, not Britain or Germany.

Contemporary, large-scale research in limiting gun violence is essentially nonexistent since a 1993 Centers for Disease Control and Prevention (CDC) funded study found a link between keeping a gun in the home with an increased risk of homicide. Quick to respond, Congress passed the 1996 Dickey Amendment that prohibits the CDC from funding efforts that “advocate or promote gun control.” This amendment has been renewed every year despite the author of the bill, Representative Jay Dickey, expressing regret for halting all gun research, stating that was not his intention. Rep. Dickey died earlier this year.

In the U.S., gun laws have actually relaxed over time. In 1988, 18 states had laws allowing civilians to carry concealed hand guns in public places, now this practice is legal in 40 states. In a 2008 landmark decision, the Supreme Court struck down a personal handgun ban in the District of Columbia. The Second Amendment rights afforded to a “well-regulated militia” to “keep and bear arms” were now extended to private individuals. Guns are clearly more prevalent and available in the U.S. than ever before.

The congressional ban on firearms research now extends to all Department of Health and Human Services agencies, including the NIH. We need the Dickey Amendment lifted so we can study the relationship of gun ownership and crime. As physicians, we need to deal from an informed, intelligent position and not an emotional one.

Over 50 medical societies, comprising essentially every physician in the U.S., have released statements on gun violence. The AMA has labeled it a “public health crisis.” The ACS stated, in the aftermath of the Las Vegas shooting, “It is important that the American College of Surgeons, whose Fellows care for the victims of these events, be part of the solution.”

Aside from ethical or moral obligations, why should we dive into this quagmire? Most of us are already represented in the discussion through other groups. The answer lies in our identity. If vascular surgery is to become a truly independent specialty, we can’t hide behind the ACS or the AMA when the politics become sticky.

To protect the 30,000 people who die from aneurysm rupture yearly we literally forced an act of Congress. Where do we stand on the more than 33,000 people who die yearly from gun violence? For vascular surgery to have a true public presence, we must be prepared to enter the most public of all discussions.

Luckily, there is already a pathway to consensus. The American College of Surgeons Committee on Trauma (ACS COT) surveyed its members and found that only 15% had no strong opinions on firearms. Just over 50% felt that guns were important for personal safety and defense, while 30% felt the large number of guns in the U.S. was a threat to safety.

Individuals who felt that firearms were important were most likely to associate guns with personal freedom, while those who felt they were a threat were most likely to associate guns with violence.

To further the discussion, the emotional battle between personal freedom and violence needed to be minimized. In doing so, the ACS COT was able to produce a consensus statement despite the seemingly diametrically opposed opinions of its members.

An independent specialty needs an independent voice. If we don’t know our own position, obviously the public doesn’t either.

As a starting point, here is the ACS Statement on Firearms Injuries:

Because violence inflicted by guns continues to be a daily event in the United States and mass casualties involving firearms threaten the health and safety of the public, the American College of Surgeons supports:

1. Legislation banning civilian access to assault weapons, large ammunition clips, and munitions designed for military and law enforcement agencies.

2. Enhancing mandatory background checks for the purchase of firearms to include gun shows and auctions.

3. Assuring that health care professionals can fulfill their role in preventing firearm injuries by health screening, patient counseling, and referral to mental health services for those with behavioral medical conditions. 4. Developing and promoting proactive programs directed at improving safe gun storage and the teaching of nonviolent conflict resolution for a culture that often glorifies guns and violence in media and gaming.

5. Evidence-based research on firearm injury and the creation of a national firearm injury database to inform federal health policy. 

Selected References

1) Gun Violence Research: History of Federal Funding Freeze (www.apa.org/science/about/psa/2013/02/gun-violence.aspx)

2) Childhood Firearm Injuries in the United States (www.apa.org/science/about/psa/2013/02/gun-violence.aspx)

3) Gun Violence Letter to the U.S. House of Representatives (2013) (www.acponline.org/acp_policy/letters/gun_violence_letter_house_2013.pdf)

4) Survey of American College of Surgeons Committee on Trauma members on firearm injury: Consensus and opportunities (2016) (www.facs.org).

5) American College of Surgeons Statement on Firearm Injuries (www.facs.org)

Studies have shown that most of you already have deep-seated beliefs regarding guns. Some of you would frame the issue as Gun Rights, others as Gun Violence. I am not here to change your opinion. I am not in the habit of wasting my time. Logic has been drained from this discussion and emotion infused. As vascular surgeons, it is far past time to overcome these limitations and join the national discussion. Opinions and consensus statements have already been rendered from the American College of Surgeons, the American Medical Association, the American Academy of Pediatrics, the Society of Thoracic Surgeons, and even the American College of Phlebology. Where does the SVS stand?

In January 2013, the Board of Directors of the SVS voted to support the ACS Statement on Firearm Injuries. There is virtually no public record of this endorsement, it does not appear on the SVS website and it was essentially ignored by the public.

Even the diligent National Rifle Association (NRA) left the SVS off their list of “National Organizations with Anti-Gun Policies” (Ed note: for more information, see “The Evolution of the NRA and Our Modern Gun Debate” at www.vascularspecialistonline.com).

We need to do better. If we are truly an independent specialty it is time to behave as such. Vascular surgeons are on the front lines of this battle. We have cared for the injured, revived the dying, and bear witness to the dead. To not have a voice and be counted is a disservice to our patients and ourselves.

What can be done to reduce gun violence? In Australia, between 1979 and 1996, there were 13 mass shootings. After a semiautomatic weapon ban was instituted in 1996 there have been none. The U.S. ban on military style weapons lapsed in 2004. While it is difficult to characterize “mass shootings” in a country our size, there certainly seems to be an increase since then. If defined as “four or more shot and/or killed in a single event, at the same general time and location not including the shooter,” then we have seen 275 mass shootings this year as of Oct. 5, 2017.

The other statistics are familiar and sobering. More Americans have died from guns since 1968 than have died in all the wars since our country’s inception. The United States accounts for 91% of gun deaths of children among developed countries. Our casualty figures more closely mirror Somalia and Honduras, not Britain or Germany.

Contemporary, large-scale research in limiting gun violence is essentially nonexistent since a 1993 Centers for Disease Control and Prevention (CDC) funded study found a link between keeping a gun in the home with an increased risk of homicide. Quick to respond, Congress passed the 1996 Dickey Amendment that prohibits the CDC from funding efforts that “advocate or promote gun control.” This amendment has been renewed every year despite the author of the bill, Representative Jay Dickey, expressing regret for halting all gun research, stating that was not his intention. Rep. Dickey died earlier this year.

In the U.S., gun laws have actually relaxed over time. In 1988, 18 states had laws allowing civilians to carry concealed hand guns in public places, now this practice is legal in 40 states. In a 2008 landmark decision, the Supreme Court struck down a personal handgun ban in the District of Columbia. The Second Amendment rights afforded to a “well-regulated militia” to “keep and bear arms” were now extended to private individuals. Guns are clearly more prevalent and available in the U.S. than ever before.

The congressional ban on firearms research now extends to all Department of Health and Human Services agencies, including the NIH. We need the Dickey Amendment lifted so we can study the relationship of gun ownership and crime. As physicians, we need to deal from an informed, intelligent position and not an emotional one.

Over 50 medical societies, comprising essentially every physician in the U.S., have released statements on gun violence. The AMA has labeled it a “public health crisis.” The ACS stated, in the aftermath of the Las Vegas shooting, “It is important that the American College of Surgeons, whose Fellows care for the victims of these events, be part of the solution.”

Aside from ethical or moral obligations, why should we dive into this quagmire? Most of us are already represented in the discussion through other groups. The answer lies in our identity. If vascular surgery is to become a truly independent specialty, we can’t hide behind the ACS or the AMA when the politics become sticky.

To protect the 30,000 people who die from aneurysm rupture yearly we literally forced an act of Congress. Where do we stand on the more than 33,000 people who die yearly from gun violence? For vascular surgery to have a true public presence, we must be prepared to enter the most public of all discussions.

Luckily, there is already a pathway to consensus. The American College of Surgeons Committee on Trauma (ACS COT) surveyed its members and found that only 15% had no strong opinions on firearms. Just over 50% felt that guns were important for personal safety and defense, while 30% felt the large number of guns in the U.S. was a threat to safety.

Individuals who felt that firearms were important were most likely to associate guns with personal freedom, while those who felt they were a threat were most likely to associate guns with violence.

To further the discussion, the emotional battle between personal freedom and violence needed to be minimized. In doing so, the ACS COT was able to produce a consensus statement despite the seemingly diametrically opposed opinions of its members.

An independent specialty needs an independent voice. If we don’t know our own position, obviously the public doesn’t either.

As a starting point, here is the ACS Statement on Firearms Injuries:

Because violence inflicted by guns continues to be a daily event in the United States and mass casualties involving firearms threaten the health and safety of the public, the American College of Surgeons supports:

1. Legislation banning civilian access to assault weapons, large ammunition clips, and munitions designed for military and law enforcement agencies.

2. Enhancing mandatory background checks for the purchase of firearms to include gun shows and auctions.

3. Assuring that health care professionals can fulfill their role in preventing firearm injuries by health screening, patient counseling, and referral to mental health services for those with behavioral medical conditions. 4. Developing and promoting proactive programs directed at improving safe gun storage and the teaching of nonviolent conflict resolution for a culture that often glorifies guns and violence in media and gaming.

5. Evidence-based research on firearm injury and the creation of a national firearm injury database to inform federal health policy. 

Selected References

1) Gun Violence Research: History of Federal Funding Freeze (www.apa.org/science/about/psa/2013/02/gun-violence.aspx)

2) Childhood Firearm Injuries in the United States (www.apa.org/science/about/psa/2013/02/gun-violence.aspx)

3) Gun Violence Letter to the U.S. House of Representatives (2013) (www.acponline.org/acp_policy/letters/gun_violence_letter_house_2013.pdf)

4) Survey of American College of Surgeons Committee on Trauma members on firearm injury: Consensus and opportunities (2016) (www.facs.org).

5) American College of Surgeons Statement on Firearm Injuries (www.facs.org)

Studies have shown that most of you already have deep-seated beliefs regarding guns. Some of you would frame the issue as Gun Rights, others as Gun Violence. I am not here to change your opinion. I am not in the habit of wasting my time. Logic has been drained from this discussion and emotion infused. As vascular surgeons, it is far past time to overcome these limitations and join the national discussion. Opinions and consensus statements have already been rendered from the American College of Surgeons, the American Medical Association, the American Academy of Pediatrics, the Society of Thoracic Surgeons, and even the American College of Phlebology. Where does the SVS stand?

In January 2013, the Board of Directors of the SVS voted to support the ACS Statement on Firearm Injuries. There is virtually no public record of this endorsement, it does not appear on the SVS website and it was essentially ignored by the public.

Even the diligent National Rifle Association (NRA) left the SVS off their list of “National Organizations with Anti-Gun Policies” (Ed note: for more information, see “The Evolution of the NRA and Our Modern Gun Debate” at www.vascularspecialistonline.com).

We need to do better. If we are truly an independent specialty it is time to behave as such. Vascular surgeons are on the front lines of this battle. We have cared for the injured, revived the dying, and bear witness to the dead. To not have a voice and be counted is a disservice to our patients and ourselves.

What can be done to reduce gun violence? In Australia, between 1979 and 1996, there were 13 mass shootings. After a semiautomatic weapon ban was instituted in 1996 there have been none. The U.S. ban on military style weapons lapsed in 2004. While it is difficult to characterize “mass shootings” in a country our size, there certainly seems to be an increase since then. If defined as “four or more shot and/or killed in a single event, at the same general time and location not including the shooter,” then we have seen 275 mass shootings this year as of Oct. 5, 2017.

The other statistics are familiar and sobering. More Americans have died from guns since 1968 than have died in all the wars since our country’s inception. The United States accounts for 91% of gun deaths of children among developed countries. Our casualty figures more closely mirror Somalia and Honduras, not Britain or Germany.

Contemporary, large-scale research in limiting gun violence is essentially nonexistent since a 1993 Centers for Disease Control and Prevention (CDC) funded study found a link between keeping a gun in the home with an increased risk of homicide. Quick to respond, Congress passed the 1996 Dickey Amendment that prohibits the CDC from funding efforts that “advocate or promote gun control.” This amendment has been renewed every year despite the author of the bill, Representative Jay Dickey, expressing regret for halting all gun research, stating that was not his intention. Rep. Dickey died earlier this year.

In the U.S., gun laws have actually relaxed over time. In 1988, 18 states had laws allowing civilians to carry concealed hand guns in public places, now this practice is legal in 40 states. In a 2008 landmark decision, the Supreme Court struck down a personal handgun ban in the District of Columbia. The Second Amendment rights afforded to a “well-regulated militia” to “keep and bear arms” were now extended to private individuals. Guns are clearly more prevalent and available in the U.S. than ever before.

The congressional ban on firearms research now extends to all Department of Health and Human Services agencies, including the NIH. We need the Dickey Amendment lifted so we can study the relationship of gun ownership and crime. As physicians, we need to deal from an informed, intelligent position and not an emotional one.

Over 50 medical societies, comprising essentially every physician in the U.S., have released statements on gun violence. The AMA has labeled it a “public health crisis.” The ACS stated, in the aftermath of the Las Vegas shooting, “It is important that the American College of Surgeons, whose Fellows care for the victims of these events, be part of the solution.”

Aside from ethical or moral obligations, why should we dive into this quagmire? Most of us are already represented in the discussion through other groups. The answer lies in our identity. If vascular surgery is to become a truly independent specialty, we can’t hide behind the ACS or the AMA when the politics become sticky.

To protect the 30,000 people who die from aneurysm rupture yearly we literally forced an act of Congress. Where do we stand on the more than 33,000 people who die yearly from gun violence? For vascular surgery to have a true public presence, we must be prepared to enter the most public of all discussions.

Luckily, there is already a pathway to consensus. The American College of Surgeons Committee on Trauma (ACS COT) surveyed its members and found that only 15% had no strong opinions on firearms. Just over 50% felt that guns were important for personal safety and defense, while 30% felt the large number of guns in the U.S. was a threat to safety.

Individuals who felt that firearms were important were most likely to associate guns with personal freedom, while those who felt they were a threat were most likely to associate guns with violence.

To further the discussion, the emotional battle between personal freedom and violence needed to be minimized. In doing so, the ACS COT was able to produce a consensus statement despite the seemingly diametrically opposed opinions of its members.

An independent specialty needs an independent voice. If we don’t know our own position, obviously the public doesn’t either.

As a starting point, here is the ACS Statement on Firearms Injuries:

Because violence inflicted by guns continues to be a daily event in the United States and mass casualties involving firearms threaten the health and safety of the public, the American College of Surgeons supports:

1. Legislation banning civilian access to assault weapons, large ammunition clips, and munitions designed for military and law enforcement agencies.

2. Enhancing mandatory background checks for the purchase of firearms to include gun shows and auctions.

3. Assuring that health care professionals can fulfill their role in preventing firearm injuries by health screening, patient counseling, and referral to mental health services for those with behavioral medical conditions. 4. Developing and promoting proactive programs directed at improving safe gun storage and the teaching of nonviolent conflict resolution for a culture that often glorifies guns and violence in media and gaming.

5. Evidence-based research on firearm injury and the creation of a national firearm injury database to inform federal health policy. 

Selected References

1) Gun Violence Research: History of Federal Funding Freeze (www.apa.org/science/about/psa/2013/02/gun-violence.aspx)

2) Childhood Firearm Injuries in the United States (www.apa.org/science/about/psa/2013/02/gun-violence.aspx)

3) Gun Violence Letter to the U.S. House of Representatives (2013) (www.acponline.org/acp_policy/letters/gun_violence_letter_house_2013.pdf)

4) Survey of American College of Surgeons Committee on Trauma members on firearm injury: Consensus and opportunities (2016) (www.facs.org).

5) American College of Surgeons Statement on Firearm Injuries (www.facs.org)

Most mature surgeons and surgical educators have been asked by hopeful young medical students: “What can I do to improve my chances of becoming a surgeon?” We all want to give our aspiring students encouraging yet truthful answers. The following are typical questions we get from students, and we have tried to provide responses that are both helpful and realistic given the individual circumstances. Do young hopefuls query you about what it takes to become a surgeon? If so, we invite you to let us know what kinds of questions you get and how you respond. We all want “the best and the brightest” to join our profession, and we can help make that happen by offering sound advice to those who come to us asking “How can I become a surgeon?”

Dear Dr. Hughes,

I am a first-year medical student and want to become a surgeon! Everyone tells me I have to have at least two publications to even be considered for an interview. Is this true? What is the best area of research for me to pursue to assure a match in a surgery residency?

Unpublished in the Midwest


Dear Unpublished,

Like almost everything in life, the answer to your question is “It depends.” Surgery is a field that covers such a wide range of opportunities and training options that there is no “perfect” path to residency. More than anything at the M1 level, you need to keep your options open for any discipline. During the next 3 years, you’ll find out much about yourself and about the breadth of medicine. You need to understand who you are as a person before deciding on a specialty and especially before embarking on a research project. Research is a crucial part of surgery, but research just to have a publication for your resume is not a good enough reason to take this on during medical school.

The pursuit of knowledge through research is best undertaken because you have a passion for a particular subject. Most program directors will see right through “insincere” research – that is, research done to puff up a resume but lacking underlying value or relevance to your personal interests.

Most mature surgeons and surgical educators have been asked by hopeful young medical students: “What can I do to improve my chances of becoming a surgeon?” We all want to give our aspiring students encouraging yet truthful answers. The following are typical questions we get from students, and we have tried to provide responses that are both helpful and realistic given the individual circumstances. Do young hopefuls query you about what it takes to become a surgeon? If so, we invite you to let us know what kinds of questions you get and how you respond. We all want “the best and the brightest” to join our profession, and we can help make that happen by offering sound advice to those who come to us asking “How can I become a surgeon?”

Dear Dr. Hughes,

I am a first-year medical student and want to become a surgeon! Everyone tells me I have to have at least two publications to even be considered for an interview. Is this true? What is the best area of research for me to pursue to assure a match in a surgery residency?

Unpublished in the Midwest


Dear Unpublished,

Like almost everything in life, the answer to your question is “It depends.” Surgery is a field that covers such a wide range of opportunities and training options that there is no “perfect” path to residency. More than anything at the M1 level, you need to keep your options open for any discipline. During the next 3 years, you’ll find out much about yourself and about the breadth of medicine. You need to understand who you are as a person before deciding on a specialty and especially before embarking on a research project. Research is a crucial part of surgery, but research just to have a publication for your resume is not a good enough reason to take this on during medical school.

The pursuit of knowledge through research is best undertaken because you have a passion for a particular subject. Most program directors will see right through “insincere” research – that is, research done to puff up a resume but lacking underlying value or relevance to your personal interests.

Most mature surgeons and surgical educators have been asked by hopeful young medical students: “What can I do to improve my chances of becoming a surgeon?” We all want to give our aspiring students encouraging yet truthful answers. The following are typical questions we get from students, and we have tried to provide responses that are both helpful and realistic given the individual circumstances. Do young hopefuls query you about what it takes to become a surgeon? If so, we invite you to let us know what kinds of questions you get and how you respond. We all want “the best and the brightest” to join our profession, and we can help make that happen by offering sound advice to those who come to us asking “How can I become a surgeon?”

Dear Dr. Hughes,

I am a first-year medical student and want to become a surgeon! Everyone tells me I have to have at least two publications to even be considered for an interview. Is this true? What is the best area of research for me to pursue to assure a match in a surgery residency?

Unpublished in the Midwest


Dear Unpublished,

Like almost everything in life, the answer to your question is “It depends.” Surgery is a field that covers such a wide range of opportunities and training options that there is no “perfect” path to residency. More than anything at the M1 level, you need to keep your options open for any discipline. During the next 3 years, you’ll find out much about yourself and about the breadth of medicine. You need to understand who you are as a person before deciding on a specialty and especially before embarking on a research project. Research is a crucial part of surgery, but research just to have a publication for your resume is not a good enough reason to take this on during medical school.

The pursuit of knowledge through research is best undertaken because you have a passion for a particular subject. Most program directors will see right through “insincere” research – that is, research done to puff up a resume but lacking underlying value or relevance to your personal interests.

The Sarcoma Journal — Official Journal of the Sarcoma Foundation of America™ represents a new and exciting initiative in professional education. We invite you to share in the excitement surrounding the launch of a medical journal designed to be your most authoritative and comprehensive source of scientific information on the diagnosis and treatment of sarcomas and sarcoma sub-types.

On behalf of myself, our editorial board, and editorial staff, I welcome you to this journal as we explore new treatment paradigms for this disease, translational research that bridges the bench and the clinic, and a broad range of science to encompass the many facets of sarcoma. In my opinion, the startup of this publication could not come at a better time.

As cancer specialists and allied health care professionals who attend regular meetings of your peers, including ASCO and CTOS, we have seen a dramatic shift in management within the last few years. In many ways we are at a threshold of a new era in sarcoma management, and the spectrum of treatment is expanding across subspecialties, promising more effective strategies for our patients that are based on an improved understanding of disease biology. We need a resource to maintain and clarify our focus on this disease as research opens new avenues for us to consider in the management of patients with sarcoma.

When I was approached to serve as Editor-in-Chief of The Sarcoma Journal by the Sarcoma Foundation of America, I began to recruit an esteemed group of colleagues whose knowledge, worldwide reputation as thought leaders, and dedicated work as researchers would reflect our commitment toward finding a cure for sarcoma. Many of the colleagues who will join me on the Editorial Advisory Board have long-standing affiliations with the Sarcoma Foundation of America and its comprehensive program of sarcoma research, patient support and education and advocacy. As you explore the first issue of the journal, you will discover how our editorial content is an extension of this three-tiered approach. The SFA program is characterized by a multi-dimensional and uniquely coordinated outreach program of videos and webinars, websites (a new journal website is launching as well) a sarcoma-specific clinical trials database, newsletters and related materials— all aimed ultimately at finding a cure for this disease. This professional journal complements and extends the SFA’s mission.

Although The Sarcoma Journal has a position within the SFA umbrella, my focus is foremost on ensuring that The Sarcoma Journal contains the most accurate, relevant and up to date information available. I urge you to explore our highly informative and relevant sarcoma-specific content—including original reports, review articles, a Journal Club, expert opinion, meeting reports, and patient advocacy that encapsulates the latest findings from the bench with implications for the bedside.

Whether it is discussing the latest findings in advanced sarcoma sub-types or implications of genetics as a prognostic factor, you will find the information in this journal, reliably analyzed by our team of experts who are leading sarcoma clinicians and investigators. All of the content we provide is presented in a thought-provoking, lively and peer-reviewed format; we welcome your comments and suggestions to keep us on the forefront of patient care as we cover a rapidly evolving landscape of new information in the treatment of sarcomas and frame it within a context directly applicable to enhancing the quality of patient care.

The Sarcoma Journal — Official Journal of the Sarcoma Foundation of America™ represents a new and exciting initiative in professional education. We invite you to share in the excitement surrounding the launch of a medical journal designed to be your most authoritative and comprehensive source of scientific information on the diagnosis and treatment of sarcomas and sarcoma sub-types.

On behalf of myself, our editorial board, and editorial staff, I welcome you to this journal as we explore new treatment paradigms for this disease, translational research that bridges the bench and the clinic, and a broad range of science to encompass the many facets of sarcoma. In my opinion, the startup of this publication could not come at a better time.

As cancer specialists and allied health care professionals who attend regular meetings of your peers, including ASCO and CTOS, we have seen a dramatic shift in management within the last few years. In many ways we are at a threshold of a new era in sarcoma management, and the spectrum of treatment is expanding across subspecialties, promising more effective strategies for our patients that are based on an improved understanding of disease biology. We need a resource to maintain and clarify our focus on this disease as research opens new avenues for us to consider in the management of patients with sarcoma.

When I was approached to serve as Editor-in-Chief of The Sarcoma Journal by the Sarcoma Foundation of America, I began to recruit an esteemed group of colleagues whose knowledge, worldwide reputation as thought leaders, and dedicated work as researchers would reflect our commitment toward finding a cure for sarcoma. Many of the colleagues who will join me on the Editorial Advisory Board have long-standing affiliations with the Sarcoma Foundation of America and its comprehensive program of sarcoma research, patient support and education and advocacy. As you explore the first issue of the journal, you will discover how our editorial content is an extension of this three-tiered approach. The SFA program is characterized by a multi-dimensional and uniquely coordinated outreach program of videos and webinars, websites (a new journal website is launching as well) a sarcoma-specific clinical trials database, newsletters and related materials— all aimed ultimately at finding a cure for this disease. This professional journal complements and extends the SFA’s mission.

Although The Sarcoma Journal has a position within the SFA umbrella, my focus is foremost on ensuring that The Sarcoma Journal contains the most accurate, relevant and up to date information available. I urge you to explore our highly informative and relevant sarcoma-specific content—including original reports, review articles, a Journal Club, expert opinion, meeting reports, and patient advocacy that encapsulates the latest findings from the bench with implications for the bedside.

Whether it is discussing the latest findings in advanced sarcoma sub-types or implications of genetics as a prognostic factor, you will find the information in this journal, reliably analyzed by our team of experts who are leading sarcoma clinicians and investigators. All of the content we provide is presented in a thought-provoking, lively and peer-reviewed format; we welcome your comments and suggestions to keep us on the forefront of patient care as we cover a rapidly evolving landscape of new information in the treatment of sarcomas and frame it within a context directly applicable to enhancing the quality of patient care.

The Sarcoma Journal — Official Journal of the Sarcoma Foundation of America™ represents a new and exciting initiative in professional education. We invite you to share in the excitement surrounding the launch of a medical journal designed to be your most authoritative and comprehensive source of scientific information on the diagnosis and treatment of sarcomas and sarcoma sub-types.

On behalf of myself, our editorial board, and editorial staff, I welcome you to this journal as we explore new treatment paradigms for this disease, translational research that bridges the bench and the clinic, and a broad range of science to encompass the many facets of sarcoma. In my opinion, the startup of this publication could not come at a better time.

As cancer specialists and allied health care professionals who attend regular meetings of your peers, including ASCO and CTOS, we have seen a dramatic shift in management within the last few years. In many ways we are at a threshold of a new era in sarcoma management, and the spectrum of treatment is expanding across subspecialties, promising more effective strategies for our patients that are based on an improved understanding of disease biology. We need a resource to maintain and clarify our focus on this disease as research opens new avenues for us to consider in the management of patients with sarcoma.

When I was approached to serve as Editor-in-Chief of The Sarcoma Journal by the Sarcoma Foundation of America, I began to recruit an esteemed group of colleagues whose knowledge, worldwide reputation as thought leaders, and dedicated work as researchers would reflect our commitment toward finding a cure for sarcoma. Many of the colleagues who will join me on the Editorial Advisory Board have long-standing affiliations with the Sarcoma Foundation of America and its comprehensive program of sarcoma research, patient support and education and advocacy. As you explore the first issue of the journal, you will discover how our editorial content is an extension of this three-tiered approach. The SFA program is characterized by a multi-dimensional and uniquely coordinated outreach program of videos and webinars, websites (a new journal website is launching as well) a sarcoma-specific clinical trials database, newsletters and related materials— all aimed ultimately at finding a cure for this disease. This professional journal complements and extends the SFA’s mission.

Although The Sarcoma Journal has a position within the SFA umbrella, my focus is foremost on ensuring that The Sarcoma Journal contains the most accurate, relevant and up to date information available. I urge you to explore our highly informative and relevant sarcoma-specific content—including original reports, review articles, a Journal Club, expert opinion, meeting reports, and patient advocacy that encapsulates the latest findings from the bench with implications for the bedside.

Whether it is discussing the latest findings in advanced sarcoma sub-types or implications of genetics as a prognostic factor, you will find the information in this journal, reliably analyzed by our team of experts who are leading sarcoma clinicians and investigators. All of the content we provide is presented in a thought-provoking, lively and peer-reviewed format; we welcome your comments and suggestions to keep us on the forefront of patient care as we cover a rapidly evolving landscape of new information in the treatment of sarcomas and frame it within a context directly applicable to enhancing the quality of patient care.

The successful interplay between the host defense system and infectious invaders depends on controlling the tissue damage that ensues from both the infection and the resultant inflammatory response. Even though an underactive immune system predisposes to unusual and potentially severe infections, an overly vigorous host response to infection can be as destructive as the infection itself. We can improve the outcome of some infections by introducing potent anti-inflammatory and immunosuppressive therapy concurrent with appropriate anti-infective therapy. What initially seemed counterintuitive has become the standard of care in the treatment of bacterial and mycobacterial meningitis and severe Pneumocystis and bacterial pneumonias, and favorable data are accruing in other infections such as bacterial arthritis.

A twist on the above scenario can occur when an immunosuppressed patient with a partially controlled indolent infection has his or her immune system suddenly normalized due to successful treatment of the underlying cause of their immunodeficiency. This treatment may be the introduction of successful antiretroviral therapy against human immunodeficiency virus (HIV), effective therapy of an immunosuppressing infection like tuberculosis, or withdrawal of an immunosuppressive anti-tumor necrosis factor (anti-TNF) drug. In this scenario, where the immune system is rapidly reconstituted and concurrently activated by the presence of persistent antigenic challenge or immunostimulatory molecules, a vigorous and clinically counterproductive inflammatory response may ensue, causing “collateral damage” to normal tissue. This immune reactivation syndrome may include fever, sweats, adenitis, and local tissue destruction at the site of infectious agents and associated phlogistic breakdown products. The result of this robust, tissue-injurious inflammatory response can be particularly devastating if it occurs in the brain or the retina, and may cause diagnostic confusion.

The trigger for this regional and systemic inflammatory response is multifactorial. It includes the newly recovered responsiveness to high levels of circulating cytokines, reaction to immune-stimulating fatty acids and other molecules released from dying mycobacteria (perhaps akin to the Jarisch-Herxheimer reaction to rapidly dying spirochetes), and possibly an over-vigorous “rebooting” immune system if an appropriate regulatory cell network is yet to be reconstituted.

In this issue of the Journal, Hara et al provide images from a patient appropriately treated for tuberculosis who experienced continued systemic symptoms of infection with the appearance of new pulmonary lesions. The trigger was the withdrawal of the infliximab (anti-TNF) therapy he was taking for ulcerative colitis, which at face value might be expected to facilitate the successful treatment of his tuberculosis. This seemingly paradoxical reaction has been well described with the successful treatment of HIV-infected patients coinfected with mycobacteria (tuberculous or nontuberculous), cytomegalovirus, and herpes-associated Kaposi sarcoma and zoster. But as in this instructive description of a patient with an immune reactivation syndrome, it also occurs in the setting of non-HIV reversibly immunosuppressed patients.^1,2 The syndrome is often recognized 1 to 2 months after immune reconstitution and the initiation of anti-infective therapy.

The treatment of this paradoxical reaction is (not so paradoxically) the administration of corticosteroids or other immunosuppressive drugs. The efficacy of corticosteroids has been demonstrated in a small placebo-controlled trial³ as well as in clinical practice. The mechanism driving this reaction may not be the same for all infections, and thus steroids may not be ideal treatment for all patients. There are reports of using infliximab to temper the immune reactivation syndrome in some patients who did not respond to corticosteroids.

There is no definitive confirmatory test for immune reactivation syndrome. And certainly in the case of known mycobacterial infection, we must ensure the absence of drug resistance and that the appropriate antibiotics are being used, and that no additional infection is present and untreated by the antimycobacterial therapy. While lymphocytosis and an overly robust tuberculin skin test response have been described in patients with tuberculosis experiencing an immune reactivation syndrome, this “paradoxical reaction” remains a clinical diagnosis, worth considering in the appropriate setting.

The successful interplay between the host defense system and infectious invaders depends on controlling the tissue damage that ensues from both the infection and the resultant inflammatory response. Even though an underactive immune system predisposes to unusual and potentially severe infections, an overly vigorous host response to infection can be as destructive as the infection itself. We can improve the outcome of some infections by introducing potent anti-inflammatory and immunosuppressive therapy concurrent with appropriate anti-infective therapy. What initially seemed counterintuitive has become the standard of care in the treatment of bacterial and mycobacterial meningitis and severe Pneumocystis and bacterial pneumonias, and favorable data are accruing in other infections such as bacterial arthritis.

A twist on the above scenario can occur when an immunosuppressed patient with a partially controlled indolent infection has his or her immune system suddenly normalized due to successful treatment of the underlying cause of their immunodeficiency. This treatment may be the introduction of successful antiretroviral therapy against human immunodeficiency virus (HIV), effective therapy of an immunosuppressing infection like tuberculosis, or withdrawal of an immunosuppressive anti-tumor necrosis factor (anti-TNF) drug. In this scenario, where the immune system is rapidly reconstituted and concurrently activated by the presence of persistent antigenic challenge or immunostimulatory molecules, a vigorous and clinically counterproductive inflammatory response may ensue, causing “collateral damage” to normal tissue. This immune reactivation syndrome may include fever, sweats, adenitis, and local tissue destruction at the site of infectious agents and associated phlogistic breakdown products. The result of this robust, tissue-injurious inflammatory response can be particularly devastating if it occurs in the brain or the retina, and may cause diagnostic confusion.

The trigger for this regional and systemic inflammatory response is multifactorial. It includes the newly recovered responsiveness to high levels of circulating cytokines, reaction to immune-stimulating fatty acids and other molecules released from dying mycobacteria (perhaps akin to the Jarisch-Herxheimer reaction to rapidly dying spirochetes), and possibly an over-vigorous “rebooting” immune system if an appropriate regulatory cell network is yet to be reconstituted.

In this issue of the Journal, Hara et al provide images from a patient appropriately treated for tuberculosis who experienced continued systemic symptoms of infection with the appearance of new pulmonary lesions. The trigger was the withdrawal of the infliximab (anti-TNF) therapy he was taking for ulcerative colitis, which at face value might be expected to facilitate the successful treatment of his tuberculosis. This seemingly paradoxical reaction has been well described with the successful treatment of HIV-infected patients coinfected with mycobacteria (tuberculous or nontuberculous), cytomegalovirus, and herpes-associated Kaposi sarcoma and zoster. But as in this instructive description of a patient with an immune reactivation syndrome, it also occurs in the setting of non-HIV reversibly immunosuppressed patients.^1,2 The syndrome is often recognized 1 to 2 months after immune reconstitution and the initiation of anti-infective therapy.

The treatment of this paradoxical reaction is (not so paradoxically) the administration of corticosteroids or other immunosuppressive drugs. The efficacy of corticosteroids has been demonstrated in a small placebo-controlled trial³ as well as in clinical practice. The mechanism driving this reaction may not be the same for all infections, and thus steroids may not be ideal treatment for all patients. There are reports of using infliximab to temper the immune reactivation syndrome in some patients who did not respond to corticosteroids.

There is no definitive confirmatory test for immune reactivation syndrome. And certainly in the case of known mycobacterial infection, we must ensure the absence of drug resistance and that the appropriate antibiotics are being used, and that no additional infection is present and untreated by the antimycobacterial therapy. While lymphocytosis and an overly robust tuberculin skin test response have been described in patients with tuberculosis experiencing an immune reactivation syndrome, this “paradoxical reaction” remains a clinical diagnosis, worth considering in the appropriate setting.

The successful interplay between the host defense system and infectious invaders depends on controlling the tissue damage that ensues from both the infection and the resultant inflammatory response. Even though an underactive immune system predisposes to unusual and potentially severe infections, an overly vigorous host response to infection can be as destructive as the infection itself. We can improve the outcome of some infections by introducing potent anti-inflammatory and immunosuppressive therapy concurrent with appropriate anti-infective therapy. What initially seemed counterintuitive has become the standard of care in the treatment of bacterial and mycobacterial meningitis and severe Pneumocystis and bacterial pneumonias, and favorable data are accruing in other infections such as bacterial arthritis.

A twist on the above scenario can occur when an immunosuppressed patient with a partially controlled indolent infection has his or her immune system suddenly normalized due to successful treatment of the underlying cause of their immunodeficiency. This treatment may be the introduction of successful antiretroviral therapy against human immunodeficiency virus (HIV), effective therapy of an immunosuppressing infection like tuberculosis, or withdrawal of an immunosuppressive anti-tumor necrosis factor (anti-TNF) drug. In this scenario, where the immune system is rapidly reconstituted and concurrently activated by the presence of persistent antigenic challenge or immunostimulatory molecules, a vigorous and clinically counterproductive inflammatory response may ensue, causing “collateral damage” to normal tissue. This immune reactivation syndrome may include fever, sweats, adenitis, and local tissue destruction at the site of infectious agents and associated phlogistic breakdown products. The result of this robust, tissue-injurious inflammatory response can be particularly devastating if it occurs in the brain or the retina, and may cause diagnostic confusion.

The trigger for this regional and systemic inflammatory response is multifactorial. It includes the newly recovered responsiveness to high levels of circulating cytokines, reaction to immune-stimulating fatty acids and other molecules released from dying mycobacteria (perhaps akin to the Jarisch-Herxheimer reaction to rapidly dying spirochetes), and possibly an over-vigorous “rebooting” immune system if an appropriate regulatory cell network is yet to be reconstituted.

In this issue of the Journal, Hara et al provide images from a patient appropriately treated for tuberculosis who experienced continued systemic symptoms of infection with the appearance of new pulmonary lesions. The trigger was the withdrawal of the infliximab (anti-TNF) therapy he was taking for ulcerative colitis, which at face value might be expected to facilitate the successful treatment of his tuberculosis. This seemingly paradoxical reaction has been well described with the successful treatment of HIV-infected patients coinfected with mycobacteria (tuberculous or nontuberculous), cytomegalovirus, and herpes-associated Kaposi sarcoma and zoster. But as in this instructive description of a patient with an immune reactivation syndrome, it also occurs in the setting of non-HIV reversibly immunosuppressed patients.^1,2 The syndrome is often recognized 1 to 2 months after immune reconstitution and the initiation of anti-infective therapy.

The treatment of this paradoxical reaction is (not so paradoxically) the administration of corticosteroids or other immunosuppressive drugs. The efficacy of corticosteroids has been demonstrated in a small placebo-controlled trial³ as well as in clinical practice. The mechanism driving this reaction may not be the same for all infections, and thus steroids may not be ideal treatment for all patients. There are reports of using infliximab to temper the immune reactivation syndrome in some patients who did not respond to corticosteroids.

There is no definitive confirmatory test for immune reactivation syndrome. And certainly in the case of known mycobacterial infection, we must ensure the absence of drug resistance and that the appropriate antibiotics are being used, and that no additional infection is present and untreated by the antimycobacterial therapy. While lymphocytosis and an overly robust tuberculin skin test response have been described in patients with tuberculosis experiencing an immune reactivation syndrome, this “paradoxical reaction” remains a clinical diagnosis, worth considering in the appropriate setting.