Paul is 13-year-old male in seventh grade with a history of inattentive ADHD and a positive family history of depression and anxiety in his mother. He always has had a few friends, but recently they have not wanted to hang out with him; he feels like people are ignoring him. For the past 2 months, Paul’s mood has gotten very low. He feels sad and also bored because he is not enjoying anything anymore. He feels as though he is “a loser,” and as though nothing will ever get better. His grades have dropped. He has thoughts of wishing he were dead, although he has no specific plan and says he wouldn’t do it because he doesn’t want to hurt his parents. He is looking at his phone at night and gets to bed late, then doesn’t want to get up in the morning. He sleeps until noon on weekends. Appetite is increased. He doesn’t have energy to do things on the weekends.

Discussion

Paul clearly meets diagnostic criteria for depression. He feels sad and has lost pleasure in activities he used to enjoy. He has negative, hopeless thoughts, and vague thoughts of death although no specific plans. He has vegetative signs of depression with increased appetite and sleep; he likely has worse concentration than usual, given that his grades have dropped. Energy is low.

Both medications and specific types of psychotherapy are effective for treating depression in adolescents.

Meta-analyses have demonstrated the efficacy of SSRIs (fluoxetine, sertraline, citalopram, escitalopram) as well as venlafaxine, mirtazapine, and nefazodone with small to very small effect sizes.¹ A large placebo effect is seen in many of these studies, correlating with the number of study sites – a feature of many industry-sponsored studies.

John Walkup, MD, a leading researcher on both medication and psychotherapeutic interventions in children’s mood disorders, has pointed out that the quality of industry-sponsored studies (vs. National Institute of Mental Health–sponsored studies) is likely lower, with more pressure to get in large numbers of patients in a short period of time, less trained investigators leading to less clear-cut diagnoses, and other sources of bias.² This raises the question of whether we should weight NIMH-sponsored studies more heavily in meta-analyses.

A second factor to consider is the risk of harm, and a significant issue here is the question of whether suicidal ideation is increased among those patients taking SSRIs. Meta-analyses from the late 2000s, which balanced the number needed to treat vs. the number needed to harm, judged that for children under age 13 years, fluoxetine was the only antidepressant that was worth the cost-benefit ratio. However, in the past several years there has been a major improvement in the assessment of suicidal ideation in the form of the Columbia Suicide Severity Rating Scale, a standardized method of assessing the presence and significance of suicidal thoughts and behaviors. Studies that have used this assessment have found no significant increase in suicidal ideation with SSRIs vs. placebo.

The takeaway here is that the SSRIs can work, with fluoxetine, sertraline, and escitalopram leading the evidence, and that with refinements of the assessment they do not appear to increase the risk of suicidal ideation.³ Of course, it remains important to discuss this issue with families.

Flamingo_Photography/Getty Images

Psychotherapy is the other major treatment for depression. Cognitive behavioral therapy (CBT) and Interpersonal therapy (IPT) for adolescents show effectiveness in teens.⁴ Recent meta-analyses have gotten stronger through the use of stringent quality criteria and the inclusion of negative studies; these therapies continue to be considered well established. It is worthwhile to talk to therapists in your community to understand what type of treatment they offer. If you are hiring therapists to be embedded in your practice, look for people who have been trained in CBT or IPT. It is particularly helpful to know whether therapists have seen patients using CBT or IPT while getting supervision in these modalities.

CBT and IPT are different. CBT puts an emphasis on the thought-feeling-behavior triangle while IPT focuses more on relationships. Someone who has tried one and has not benefited nevertheless may benefit from the other.

Working with your patients to choose what type of psychotherapy modality for depression they would like is particularly effective.

Finally, be aware of how the environment may be affecting your patient. School issues related to peers, learning style or disabilities, and organization have a major effect on teens. In this case, Paul is looking at his phone nightly, which may be affecting both his sleep and self-esteem. Family issues continue to play a key role.

Dr. Hall is assistant professor of psychiatry and pediatrics at the University of Vermont, Burlington. She said she had no relevant financial disclosures. Email her at pdnews@mdedge.com.

References

1. JAMA. 2007 Apr 18;297(15):1683-96.

2. Am J Psychiatry. 2017 May 1;174(5):430-7.

3. J Child Adolesc Psychopharmacol. 2018. doi: 10.1089/cap.2017.0174.

4. J Clin Child Adolesc Psychol. 2017 Jan-Feb;46(1):11-43.

Paul is 13-year-old male in seventh grade with a history of inattentive ADHD and a positive family history of depression and anxiety in his mother. He always has had a few friends, but recently they have not wanted to hang out with him; he feels like people are ignoring him. For the past 2 months, Paul’s mood has gotten very low. He feels sad and also bored because he is not enjoying anything anymore. He feels as though he is “a loser,” and as though nothing will ever get better. His grades have dropped. He has thoughts of wishing he were dead, although he has no specific plan and says he wouldn’t do it because he doesn’t want to hurt his parents. He is looking at his phone at night and gets to bed late, then doesn’t want to get up in the morning. He sleeps until noon on weekends. Appetite is increased. He doesn’t have energy to do things on the weekends.

Discussion

Paul clearly meets diagnostic criteria for depression. He feels sad and has lost pleasure in activities he used to enjoy. He has negative, hopeless thoughts, and vague thoughts of death although no specific plans. He has vegetative signs of depression with increased appetite and sleep; he likely has worse concentration than usual, given that his grades have dropped. Energy is low.

Both medications and specific types of psychotherapy are effective for treating depression in adolescents.

Meta-analyses have demonstrated the efficacy of SSRIs (fluoxetine, sertraline, citalopram, escitalopram) as well as venlafaxine, mirtazapine, and nefazodone with small to very small effect sizes.¹ A large placebo effect is seen in many of these studies, correlating with the number of study sites – a feature of many industry-sponsored studies.

John Walkup, MD, a leading researcher on both medication and psychotherapeutic interventions in children’s mood disorders, has pointed out that the quality of industry-sponsored studies (vs. National Institute of Mental Health–sponsored studies) is likely lower, with more pressure to get in large numbers of patients in a short period of time, less trained investigators leading to less clear-cut diagnoses, and other sources of bias.² This raises the question of whether we should weight NIMH-sponsored studies more heavily in meta-analyses.

A second factor to consider is the risk of harm, and a significant issue here is the question of whether suicidal ideation is increased among those patients taking SSRIs. Meta-analyses from the late 2000s, which balanced the number needed to treat vs. the number needed to harm, judged that for children under age 13 years, fluoxetine was the only antidepressant that was worth the cost-benefit ratio. However, in the past several years there has been a major improvement in the assessment of suicidal ideation in the form of the Columbia Suicide Severity Rating Scale, a standardized method of assessing the presence and significance of suicidal thoughts and behaviors. Studies that have used this assessment have found no significant increase in suicidal ideation with SSRIs vs. placebo.

The takeaway here is that the SSRIs can work, with fluoxetine, sertraline, and escitalopram leading the evidence, and that with refinements of the assessment they do not appear to increase the risk of suicidal ideation.³ Of course, it remains important to discuss this issue with families.

Flamingo_Photography/Getty Images

Psychotherapy is the other major treatment for depression. Cognitive behavioral therapy (CBT) and Interpersonal therapy (IPT) for adolescents show effectiveness in teens.⁴ Recent meta-analyses have gotten stronger through the use of stringent quality criteria and the inclusion of negative studies; these therapies continue to be considered well established. It is worthwhile to talk to therapists in your community to understand what type of treatment they offer. If you are hiring therapists to be embedded in your practice, look for people who have been trained in CBT or IPT. It is particularly helpful to know whether therapists have seen patients using CBT or IPT while getting supervision in these modalities.

CBT and IPT are different. CBT puts an emphasis on the thought-feeling-behavior triangle while IPT focuses more on relationships. Someone who has tried one and has not benefited nevertheless may benefit from the other.

Working with your patients to choose what type of psychotherapy modality for depression they would like is particularly effective.

Finally, be aware of how the environment may be affecting your patient. School issues related to peers, learning style or disabilities, and organization have a major effect on teens. In this case, Paul is looking at his phone nightly, which may be affecting both his sleep and self-esteem. Family issues continue to play a key role.

Dr. Hall is assistant professor of psychiatry and pediatrics at the University of Vermont, Burlington. She said she had no relevant financial disclosures. Email her at pdnews@mdedge.com.

References

1. JAMA. 2007 Apr 18;297(15):1683-96.

2. Am J Psychiatry. 2017 May 1;174(5):430-7.

3. J Child Adolesc Psychopharmacol. 2018. doi: 10.1089/cap.2017.0174.

4. J Clin Child Adolesc Psychol. 2017 Jan-Feb;46(1):11-43.

Paul is 13-year-old male in seventh grade with a history of inattentive ADHD and a positive family history of depression and anxiety in his mother. He always has had a few friends, but recently they have not wanted to hang out with him; he feels like people are ignoring him. For the past 2 months, Paul’s mood has gotten very low. He feels sad and also bored because he is not enjoying anything anymore. He feels as though he is “a loser,” and as though nothing will ever get better. His grades have dropped. He has thoughts of wishing he were dead, although he has no specific plan and says he wouldn’t do it because he doesn’t want to hurt his parents. He is looking at his phone at night and gets to bed late, then doesn’t want to get up in the morning. He sleeps until noon on weekends. Appetite is increased. He doesn’t have energy to do things on the weekends.

Discussion

Paul clearly meets diagnostic criteria for depression. He feels sad and has lost pleasure in activities he used to enjoy. He has negative, hopeless thoughts, and vague thoughts of death although no specific plans. He has vegetative signs of depression with increased appetite and sleep; he likely has worse concentration than usual, given that his grades have dropped. Energy is low.

Both medications and specific types of psychotherapy are effective for treating depression in adolescents.

Meta-analyses have demonstrated the efficacy of SSRIs (fluoxetine, sertraline, citalopram, escitalopram) as well as venlafaxine, mirtazapine, and nefazodone with small to very small effect sizes.¹ A large placebo effect is seen in many of these studies, correlating with the number of study sites – a feature of many industry-sponsored studies.

John Walkup, MD, a leading researcher on both medication and psychotherapeutic interventions in children’s mood disorders, has pointed out that the quality of industry-sponsored studies (vs. National Institute of Mental Health–sponsored studies) is likely lower, with more pressure to get in large numbers of patients in a short period of time, less trained investigators leading to less clear-cut diagnoses, and other sources of bias.² This raises the question of whether we should weight NIMH-sponsored studies more heavily in meta-analyses.

A second factor to consider is the risk of harm, and a significant issue here is the question of whether suicidal ideation is increased among those patients taking SSRIs. Meta-analyses from the late 2000s, which balanced the number needed to treat vs. the number needed to harm, judged that for children under age 13 years, fluoxetine was the only antidepressant that was worth the cost-benefit ratio. However, in the past several years there has been a major improvement in the assessment of suicidal ideation in the form of the Columbia Suicide Severity Rating Scale, a standardized method of assessing the presence and significance of suicidal thoughts and behaviors. Studies that have used this assessment have found no significant increase in suicidal ideation with SSRIs vs. placebo.

The takeaway here is that the SSRIs can work, with fluoxetine, sertraline, and escitalopram leading the evidence, and that with refinements of the assessment they do not appear to increase the risk of suicidal ideation.³ Of course, it remains important to discuss this issue with families.

Flamingo_Photography/Getty Images

Psychotherapy is the other major treatment for depression. Cognitive behavioral therapy (CBT) and Interpersonal therapy (IPT) for adolescents show effectiveness in teens.⁴ Recent meta-analyses have gotten stronger through the use of stringent quality criteria and the inclusion of negative studies; these therapies continue to be considered well established. It is worthwhile to talk to therapists in your community to understand what type of treatment they offer. If you are hiring therapists to be embedded in your practice, look for people who have been trained in CBT or IPT. It is particularly helpful to know whether therapists have seen patients using CBT or IPT while getting supervision in these modalities.

CBT and IPT are different. CBT puts an emphasis on the thought-feeling-behavior triangle while IPT focuses more on relationships. Someone who has tried one and has not benefited nevertheless may benefit from the other.

Working with your patients to choose what type of psychotherapy modality for depression they would like is particularly effective.

Finally, be aware of how the environment may be affecting your patient. School issues related to peers, learning style or disabilities, and organization have a major effect on teens. In this case, Paul is looking at his phone nightly, which may be affecting both his sleep and self-esteem. Family issues continue to play a key role.

Dr. Hall is assistant professor of psychiatry and pediatrics at the University of Vermont, Burlington. She said she had no relevant financial disclosures. Email her at pdnews@mdedge.com.

References

1. JAMA. 2007 Apr 18;297(15):1683-96.

2. Am J Psychiatry. 2017 May 1;174(5):430-7.

3. J Child Adolesc Psychopharmacol. 2018. doi: 10.1089/cap.2017.0174.

4. J Clin Child Adolesc Psychol. 2017 Jan-Feb;46(1):11-43.

SAN FRANCISCO – A combination of two novel immune-stimulating agents has shown early evidence of efficacy against malignant melanoma, leiomyosarcoma, and triple-negative breast cancer in a phase 1b, dose-escalating study.

Neil Osterweil/MDedge News

Among 11 evaluable patients enrolled in a trial of NKTR-262, a small molecule agonist of toll-like receptors (TLR) 7/8, and bempegaldesleukin, an interleukin-2 pathway agonist, 2 had a partial response and 3 had stable disease, reported Adi Diab, MD, from the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.

Patients tolerated the combination well, and there have been no serious adverse events or dose-limiting toxicities.

“Pharmacodynamic data demonstrate both activation of the systemic adaptive and the local innate immune system, and we have seen early evidence of clinical activity in patients who are refractory to checkpoint inhibitors with immunotherapy regimens,” Dr. Diab said at the American Society of Clinical Oncology (ASCO) – Society for Immunotherapy of Cancer (SITC): Clinical Immuno-Oncology Symposium.

NKTR-262 is injected into tumors and is designed to be retained in the tumor microenvironment where it helps to activate antigen-presenting cells, such as dendritic cells, and primes development of new, antigen-specific cytotoxic T cells. Bempegaldesleukin is a cytokine that works within the IL-2 pathway to increase CD8-positive T cells and natural killer (NK) cells in the tumor microenvironment.

The rationale for the combination is that NKTR-262 can activate innate immunity in cells surrounding the tumor microenvironment and activate the machinery of antigen-presenting cells, and bempegaldesleukin can prime and boost a systemic tumor immune response that can ultimately mediate antitumor activity in distant lesions, Dr. Adib said.

In preclinical models, the combination of these agents led to a robust antitumor effect that also involved distant lesions through mediation of the abscopal effect, in which treatment of a tumor activates an immune response against distant tumor cells as well, Dr. Diab said.

The REVEAL study is an ongoing, phase 1b/2 trial looking at the combination in melanoma, Merkel cell carcinoma, triple-negative breast cancer (TNBC), ovarian cancer, renal cell carcinoma, colorectal cancer, urothelial carcinoma, and sarcoma.

The primary goal of the study is to evaluate safety and determine the optimal phase 2 dose of the combination, evaluate biomarkers of response, and assess antitumor activity. As of Jan. 23, 2019, 13 patients were enrolled and evaluable for safety, and 11 were evaluable for the preliminary efficacy analysis.

The most common treatment-related adverse events (TRAEs) with the combination were transient grade 1 or 2 flu-like symptoms, rash, fatigue, pruritus, and nausea. One patients developed grade 3 maculopapular rash and leukocytosis.

Most of the TRAEs are attributable to bempegaldesleukin. There were no immune-mediated AEs and no TRAEs resulted in study discontinuation.

Tumor biopsies obtained 24 hours after injection of NKTR-262 confirmed the activation of TLR 7/8 and robust induction of type 1 interferon, interferon-alpha, and interferon-beta gene-related signatures necessary for optimal antigen presentation.

Dr. Diab noted that in a different trial of bempegaldesleukin monotherapy there was no significant increase in the type 1 interferon gene signature, but the agent did promote activation of the adaptive immune system.

The complementary nature of the two novel agents could also be demonstrated in evaluation of peripheral blood samples, which showed that, although there was no proliferation of T or NK cells following NKTR-262 injection, the addition of bempegaldesleukin resulted in the proliferation of both effector T cells and NK cells to enhance the systemic immune response.

The preliminary efficacy analysis showed that two of five patients with stage IV melanoma who experienced disease progression on prior immune checkpoint inhibitors had partial responses, including one who had a 100% reduction in target lesions and the other with a 50% reduction. In addition, two patients with heavily pretreated leiomyosarcoma had stable disease as the best response, as did the single patient with TNBC.

The maximum tolerated dose of the combination has not been identified, and the investigators are continuing to enroll patients.

The REVEAL study is supported by Nektar Therapeutics. Dr. Diab reported institutional research funding, consulting fees, and advisory board participation from Nektar, Bristol-Myers Squib, Idera Pharmaceuticals, Jounce Therapeutics, and Array BioPharma.

SOURCE: Diab A et al. ASCO-SITC, Abstract 26.

SAN FRANCISCO – A combination of two novel immune-stimulating agents has shown early evidence of efficacy against malignant melanoma, leiomyosarcoma, and triple-negative breast cancer in a phase 1b, dose-escalating study.

Neil Osterweil/MDedge News

Among 11 evaluable patients enrolled in a trial of NKTR-262, a small molecule agonist of toll-like receptors (TLR) 7/8, and bempegaldesleukin, an interleukin-2 pathway agonist, 2 had a partial response and 3 had stable disease, reported Adi Diab, MD, from the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.

Patients tolerated the combination well, and there have been no serious adverse events or dose-limiting toxicities.

“Pharmacodynamic data demonstrate both activation of the systemic adaptive and the local innate immune system, and we have seen early evidence of clinical activity in patients who are refractory to checkpoint inhibitors with immunotherapy regimens,” Dr. Diab said at the American Society of Clinical Oncology (ASCO) – Society for Immunotherapy of Cancer (SITC): Clinical Immuno-Oncology Symposium.

NKTR-262 is injected into tumors and is designed to be retained in the tumor microenvironment where it helps to activate antigen-presenting cells, such as dendritic cells, and primes development of new, antigen-specific cytotoxic T cells. Bempegaldesleukin is a cytokine that works within the IL-2 pathway to increase CD8-positive T cells and natural killer (NK) cells in the tumor microenvironment.

The rationale for the combination is that NKTR-262 can activate innate immunity in cells surrounding the tumor microenvironment and activate the machinery of antigen-presenting cells, and bempegaldesleukin can prime and boost a systemic tumor immune response that can ultimately mediate antitumor activity in distant lesions, Dr. Adib said.

In preclinical models, the combination of these agents led to a robust antitumor effect that also involved distant lesions through mediation of the abscopal effect, in which treatment of a tumor activates an immune response against distant tumor cells as well, Dr. Diab said.

The REVEAL study is an ongoing, phase 1b/2 trial looking at the combination in melanoma, Merkel cell carcinoma, triple-negative breast cancer (TNBC), ovarian cancer, renal cell carcinoma, colorectal cancer, urothelial carcinoma, and sarcoma.

The primary goal of the study is to evaluate safety and determine the optimal phase 2 dose of the combination, evaluate biomarkers of response, and assess antitumor activity. As of Jan. 23, 2019, 13 patients were enrolled and evaluable for safety, and 11 were evaluable for the preliminary efficacy analysis.

The most common treatment-related adverse events (TRAEs) with the combination were transient grade 1 or 2 flu-like symptoms, rash, fatigue, pruritus, and nausea. One patients developed grade 3 maculopapular rash and leukocytosis.

Most of the TRAEs are attributable to bempegaldesleukin. There were no immune-mediated AEs and no TRAEs resulted in study discontinuation.

Tumor biopsies obtained 24 hours after injection of NKTR-262 confirmed the activation of TLR 7/8 and robust induction of type 1 interferon, interferon-alpha, and interferon-beta gene-related signatures necessary for optimal antigen presentation.

Dr. Diab noted that in a different trial of bempegaldesleukin monotherapy there was no significant increase in the type 1 interferon gene signature, but the agent did promote activation of the adaptive immune system.

The complementary nature of the two novel agents could also be demonstrated in evaluation of peripheral blood samples, which showed that, although there was no proliferation of T or NK cells following NKTR-262 injection, the addition of bempegaldesleukin resulted in the proliferation of both effector T cells and NK cells to enhance the systemic immune response.

The preliminary efficacy analysis showed that two of five patients with stage IV melanoma who experienced disease progression on prior immune checkpoint inhibitors had partial responses, including one who had a 100% reduction in target lesions and the other with a 50% reduction. In addition, two patients with heavily pretreated leiomyosarcoma had stable disease as the best response, as did the single patient with TNBC.

The maximum tolerated dose of the combination has not been identified, and the investigators are continuing to enroll patients.

The REVEAL study is supported by Nektar Therapeutics. Dr. Diab reported institutional research funding, consulting fees, and advisory board participation from Nektar, Bristol-Myers Squib, Idera Pharmaceuticals, Jounce Therapeutics, and Array BioPharma.

SOURCE: Diab A et al. ASCO-SITC, Abstract 26.

SAN FRANCISCO – A combination of two novel immune-stimulating agents has shown early evidence of efficacy against malignant melanoma, leiomyosarcoma, and triple-negative breast cancer in a phase 1b, dose-escalating study.

Neil Osterweil/MDedge News

Among 11 evaluable patients enrolled in a trial of NKTR-262, a small molecule agonist of toll-like receptors (TLR) 7/8, and bempegaldesleukin, an interleukin-2 pathway agonist, 2 had a partial response and 3 had stable disease, reported Adi Diab, MD, from the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.

Patients tolerated the combination well, and there have been no serious adverse events or dose-limiting toxicities.

“Pharmacodynamic data demonstrate both activation of the systemic adaptive and the local innate immune system, and we have seen early evidence of clinical activity in patients who are refractory to checkpoint inhibitors with immunotherapy regimens,” Dr. Diab said at the American Society of Clinical Oncology (ASCO) – Society for Immunotherapy of Cancer (SITC): Clinical Immuno-Oncology Symposium.

NKTR-262 is injected into tumors and is designed to be retained in the tumor microenvironment where it helps to activate antigen-presenting cells, such as dendritic cells, and primes development of new, antigen-specific cytotoxic T cells. Bempegaldesleukin is a cytokine that works within the IL-2 pathway to increase CD8-positive T cells and natural killer (NK) cells in the tumor microenvironment.

The rationale for the combination is that NKTR-262 can activate innate immunity in cells surrounding the tumor microenvironment and activate the machinery of antigen-presenting cells, and bempegaldesleukin can prime and boost a systemic tumor immune response that can ultimately mediate antitumor activity in distant lesions, Dr. Adib said.

In preclinical models, the combination of these agents led to a robust antitumor effect that also involved distant lesions through mediation of the abscopal effect, in which treatment of a tumor activates an immune response against distant tumor cells as well, Dr. Diab said.

The REVEAL study is an ongoing, phase 1b/2 trial looking at the combination in melanoma, Merkel cell carcinoma, triple-negative breast cancer (TNBC), ovarian cancer, renal cell carcinoma, colorectal cancer, urothelial carcinoma, and sarcoma.

The primary goal of the study is to evaluate safety and determine the optimal phase 2 dose of the combination, evaluate biomarkers of response, and assess antitumor activity. As of Jan. 23, 2019, 13 patients were enrolled and evaluable for safety, and 11 were evaluable for the preliminary efficacy analysis.

The most common treatment-related adverse events (TRAEs) with the combination were transient grade 1 or 2 flu-like symptoms, rash, fatigue, pruritus, and nausea. One patients developed grade 3 maculopapular rash and leukocytosis.

Most of the TRAEs are attributable to bempegaldesleukin. There were no immune-mediated AEs and no TRAEs resulted in study discontinuation.

Tumor biopsies obtained 24 hours after injection of NKTR-262 confirmed the activation of TLR 7/8 and robust induction of type 1 interferon, interferon-alpha, and interferon-beta gene-related signatures necessary for optimal antigen presentation.

Dr. Diab noted that in a different trial of bempegaldesleukin monotherapy there was no significant increase in the type 1 interferon gene signature, but the agent did promote activation of the adaptive immune system.

The complementary nature of the two novel agents could also be demonstrated in evaluation of peripheral blood samples, which showed that, although there was no proliferation of T or NK cells following NKTR-262 injection, the addition of bempegaldesleukin resulted in the proliferation of both effector T cells and NK cells to enhance the systemic immune response.

The preliminary efficacy analysis showed that two of five patients with stage IV melanoma who experienced disease progression on prior immune checkpoint inhibitors had partial responses, including one who had a 100% reduction in target lesions and the other with a 50% reduction. In addition, two patients with heavily pretreated leiomyosarcoma had stable disease as the best response, as did the single patient with TNBC.

The maximum tolerated dose of the combination has not been identified, and the investigators are continuing to enroll patients.

The REVEAL study is supported by Nektar Therapeutics. Dr. Diab reported institutional research funding, consulting fees, and advisory board participation from Nektar, Bristol-Myers Squib, Idera Pharmaceuticals, Jounce Therapeutics, and Array BioPharma.

SOURCE: Diab A et al. ASCO-SITC, Abstract 26.

Even the best physicians make mistakes.

Each of us can recall a patient for whom our initial diagnosis was incorrect, or conversely, where we uncovered the correct diagnosis. My memorable mistake was missing an obvious case of hypothyroidism, and my happier encounter was correcting an incorrect diagnosis of asthma when the patient actually had primary pulmonary fibrosis. These patients came to mind as I read this month’s cover story, “COPD and asthma: Diagnostic accuracy requires spirometry.”

In a previous editorial, “When our biases derail the diagnosis,”¹ I discussed types of cognitive bias that can lead us to the wrong conclusion. Today, I want to address diagnostic errors in medicine as a patient safety issue.

Listening closely to the patient's and family's concerns can lead in a direction other than my initial impression.

The patient safety movement gained traction in 1999 with the publication of the Institute of Medicine (IOM, now National Academy of Medicine) report, To Err is Human: Building a Safer Health System. That report focused on health care system issues and had little to offer regarding improving diagnoses. It was not until 2015, with the publication of the IOM report Improving Diagnosis in Health Care, that serious national attention was directed to accurate diagnosis. It is worth reading the summary of this report, which includes 8 goals and is available at nas.edu/improvingdiagnosis.

The recommendations most pertinent to family physicians are to: 1) facilitate more effective teamwork among health care professionals, patients, and families, 2) teach health care professionals about the diagnostic process, 3) ensure that technology supports proper diagnosis, 4) establish a work culture that supports diagnostic processes, and 5) identify diagnostic errors and learn from them.

Teamwork. The first recommendation is intriguing because the focus on teamwork includes patients and their families. I have found that listening closely to the patient’s and family’s concerns can lead me in a direction other than my initial impression—especially when they are insistent about a particular diagnosis.

Technology. Despite all of their “warts,” electronic health records are gradually incorporating clinical decision support tools that really do help steer us in the right direction. I have found that electronic point-of-care references can be very helpful in establishing an accurate diagnosis in the exam room—and can help convince patients that my diagnosis is correct when they read it for themselves!

Continue to: Finally, discussing our mistakes...

Finally, discussing our mistakes openly with our colleagues helps us—and them—to avoid that mistake in the future. Let’s be sure to keep that dialogue open. And let’s continue to refine our diagnostic skills so that we can continue to keep our patients safe.

Even the best physicians make mistakes.

Each of us can recall a patient for whom our initial diagnosis was incorrect, or conversely, where we uncovered the correct diagnosis. My memorable mistake was missing an obvious case of hypothyroidism, and my happier encounter was correcting an incorrect diagnosis of asthma when the patient actually had primary pulmonary fibrosis. These patients came to mind as I read this month’s cover story, “COPD and asthma: Diagnostic accuracy requires spirometry.”

In a previous editorial, “When our biases derail the diagnosis,”¹ I discussed types of cognitive bias that can lead us to the wrong conclusion. Today, I want to address diagnostic errors in medicine as a patient safety issue.

Listening closely to the patient's and family's concerns can lead in a direction other than my initial impression.

The patient safety movement gained traction in 1999 with the publication of the Institute of Medicine (IOM, now National Academy of Medicine) report, To Err is Human: Building a Safer Health System. That report focused on health care system issues and had little to offer regarding improving diagnoses. It was not until 2015, with the publication of the IOM report Improving Diagnosis in Health Care, that serious national attention was directed to accurate diagnosis. It is worth reading the summary of this report, which includes 8 goals and is available at nas.edu/improvingdiagnosis.

The recommendations most pertinent to family physicians are to: 1) facilitate more effective teamwork among health care professionals, patients, and families, 2) teach health care professionals about the diagnostic process, 3) ensure that technology supports proper diagnosis, 4) establish a work culture that supports diagnostic processes, and 5) identify diagnostic errors and learn from them.

Teamwork. The first recommendation is intriguing because the focus on teamwork includes patients and their families. I have found that listening closely to the patient’s and family’s concerns can lead me in a direction other than my initial impression—especially when they are insistent about a particular diagnosis.

Technology. Despite all of their “warts,” electronic health records are gradually incorporating clinical decision support tools that really do help steer us in the right direction. I have found that electronic point-of-care references can be very helpful in establishing an accurate diagnosis in the exam room—and can help convince patients that my diagnosis is correct when they read it for themselves!

Continue to: Finally, discussing our mistakes...

Finally, discussing our mistakes openly with our colleagues helps us—and them—to avoid that mistake in the future. Let’s be sure to keep that dialogue open. And let’s continue to refine our diagnostic skills so that we can continue to keep our patients safe.

Even the best physicians make mistakes.

Each of us can recall a patient for whom our initial diagnosis was incorrect, or conversely, where we uncovered the correct diagnosis. My memorable mistake was missing an obvious case of hypothyroidism, and my happier encounter was correcting an incorrect diagnosis of asthma when the patient actually had primary pulmonary fibrosis. These patients came to mind as I read this month’s cover story, “COPD and asthma: Diagnostic accuracy requires spirometry.”

In a previous editorial, “When our biases derail the diagnosis,”¹ I discussed types of cognitive bias that can lead us to the wrong conclusion. Today, I want to address diagnostic errors in medicine as a patient safety issue.

Listening closely to the patient's and family's concerns can lead in a direction other than my initial impression.

The patient safety movement gained traction in 1999 with the publication of the Institute of Medicine (IOM, now National Academy of Medicine) report, To Err is Human: Building a Safer Health System. That report focused on health care system issues and had little to offer regarding improving diagnoses. It was not until 2015, with the publication of the IOM report Improving Diagnosis in Health Care, that serious national attention was directed to accurate diagnosis. It is worth reading the summary of this report, which includes 8 goals and is available at nas.edu/improvingdiagnosis.

The recommendations most pertinent to family physicians are to: 1) facilitate more effective teamwork among health care professionals, patients, and families, 2) teach health care professionals about the diagnostic process, 3) ensure that technology supports proper diagnosis, 4) establish a work culture that supports diagnostic processes, and 5) identify diagnostic errors and learn from them.

Teamwork. The first recommendation is intriguing because the focus on teamwork includes patients and their families. I have found that listening closely to the patient’s and family’s concerns can lead me in a direction other than my initial impression—especially when they are insistent about a particular diagnosis.

Technology. Despite all of their “warts,” electronic health records are gradually incorporating clinical decision support tools that really do help steer us in the right direction. I have found that electronic point-of-care references can be very helpful in establishing an accurate diagnosis in the exam room—and can help convince patients that my diagnosis is correct when they read it for themselves!

Continue to: Finally, discussing our mistakes...

Finally, discussing our mistakes openly with our colleagues helps us—and them—to avoid that mistake in the future. Let’s be sure to keep that dialogue open. And let’s continue to refine our diagnostic skills so that we can continue to keep our patients safe.

DALLAS – MRI has long been important in both diagnosis and management of multiple sclerosis (MS). It’s more important than ever though, as perivenular demyelinating lesions emerge as a potential biomarker of the disease, and a key tool in precision medicine initiatives that target MS.

“The central vein sign is at the current time still a research tool that is being touted as an imaging finding that may be a very useful biomarker for diagnosis in MS,” said Jiwon Oh, MD, PhD, in an interview at the meeting presented by the Americas Committee for Treatment and Research in Multiple Sclerosis.

It’s almost ready for “prime time,” she said, “because it can easily be acquired on most conventional 3 Tesla MRI scanners, the sequences that you use don’t require an inordinate amount of time [and] it doesn’t take too much training to be able to easily identify the sign.”

A number of groups have evaluated the central vein sign and are finding it “a very specific biomarker” for MS, Dr. Oh said.

“It would be very useful in very early stages of diagnosis because it would prevent people from being misdiagnosed” and being treated unnecessarily, she said.

In her own work, Dr. Oh and her collaborators are following a cohort of people with radiologically isolated syndrome (RIS) discovered incidentally on brain imaging. “It’s a very valuable patient population to study because it may give us insight into the very earliest stages of MS,” as the lesions were not accompanied by any symptoms when they were first noticed.

Dr. Oh and her colleagues are finding that, among RIS patients, “the vast, vast majority of people have lesions with central veins; in our cohort, over 90% of patients met the 40% threshold that has been proposed to distinguish MS from other white matter changes.”

Dr. Oh said that the central vein sign may prove to be prognostic among RIS patients; they continue to follow the cohort being studied at the University of Toronto, where Dr. Oh is a neurologist.

koakes@mdedge.com

DALLAS – MRI has long been important in both diagnosis and management of multiple sclerosis (MS). It’s more important than ever though, as perivenular demyelinating lesions emerge as a potential biomarker of the disease, and a key tool in precision medicine initiatives that target MS.

“The central vein sign is at the current time still a research tool that is being touted as an imaging finding that may be a very useful biomarker for diagnosis in MS,” said Jiwon Oh, MD, PhD, in an interview at the meeting presented by the Americas Committee for Treatment and Research in Multiple Sclerosis.

It’s almost ready for “prime time,” she said, “because it can easily be acquired on most conventional 3 Tesla MRI scanners, the sequences that you use don’t require an inordinate amount of time [and] it doesn’t take too much training to be able to easily identify the sign.”

A number of groups have evaluated the central vein sign and are finding it “a very specific biomarker” for MS, Dr. Oh said.

“It would be very useful in very early stages of diagnosis because it would prevent people from being misdiagnosed” and being treated unnecessarily, she said.

In her own work, Dr. Oh and her collaborators are following a cohort of people with radiologically isolated syndrome (RIS) discovered incidentally on brain imaging. “It’s a very valuable patient population to study because it may give us insight into the very earliest stages of MS,” as the lesions were not accompanied by any symptoms when they were first noticed.

Dr. Oh and her colleagues are finding that, among RIS patients, “the vast, vast majority of people have lesions with central veins; in our cohort, over 90% of patients met the 40% threshold that has been proposed to distinguish MS from other white matter changes.”

Dr. Oh said that the central vein sign may prove to be prognostic among RIS patients; they continue to follow the cohort being studied at the University of Toronto, where Dr. Oh is a neurologist.

koakes@mdedge.com

DALLAS – MRI has long been important in both diagnosis and management of multiple sclerosis (MS). It’s more important than ever though, as perivenular demyelinating lesions emerge as a potential biomarker of the disease, and a key tool in precision medicine initiatives that target MS.

“The central vein sign is at the current time still a research tool that is being touted as an imaging finding that may be a very useful biomarker for diagnosis in MS,” said Jiwon Oh, MD, PhD, in an interview at the meeting presented by the Americas Committee for Treatment and Research in Multiple Sclerosis.

It’s almost ready for “prime time,” she said, “because it can easily be acquired on most conventional 3 Tesla MRI scanners, the sequences that you use don’t require an inordinate amount of time [and] it doesn’t take too much training to be able to easily identify the sign.”

A number of groups have evaluated the central vein sign and are finding it “a very specific biomarker” for MS, Dr. Oh said.

“It would be very useful in very early stages of diagnosis because it would prevent people from being misdiagnosed” and being treated unnecessarily, she said.

In her own work, Dr. Oh and her collaborators are following a cohort of people with radiologically isolated syndrome (RIS) discovered incidentally on brain imaging. “It’s a very valuable patient population to study because it may give us insight into the very earliest stages of MS,” as the lesions were not accompanied by any symptoms when they were first noticed.

Dr. Oh and her colleagues are finding that, among RIS patients, “the vast, vast majority of people have lesions with central veins; in our cohort, over 90% of patients met the 40% threshold that has been proposed to distinguish MS from other white matter changes.”

Dr. Oh said that the central vein sign may prove to be prognostic among RIS patients; they continue to follow the cohort being studied at the University of Toronto, where Dr. Oh is a neurologist.

koakes@mdedge.com

SNOWMASS, COLO. – When Spencer B. King III, MD, shared his thoughts about the future of interventional cardiology at the Annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology, he felt compelled to offer a cautionary note about his past accuracy as a prognosticator.

Bruce Jancin/MDedge News

It was way back at a poster session during the 1976 annual meeting of the American Heart Association in Miami Beach that he first met Andreas Gruentzig, MD, the father of percutaneous coronary intervention (PCI), who was presenting his initial revolutionary work on what he called “coronary transluminal angioplasty” in dogs.

“I looked at the poster and told him it would never work,” recalled Dr. King, professor emeritus of medicine at Emory University in Atlanta.

He soon changed his mind, however, because, to great acclaim, Dr. Gruentzig performed his successful first in-human coronary angioplasty the next year.

He noted that the Snowmass conference has played a significant role in the development of interventional cardiology in the United States. Dr. Gruentzig attended the conference in 1980, and Dr. King and others took that opportunity to persuade him to leave the bureaucratic confines of Zurich and join him at Emory later that year. The two cardiologists worked closely thereafter, refining angioplasty and conducting clinical trials until Dr. Gruentzig’s death in an airplane crash in Georgia in 1985 at age 46 years.

Turning to the future, Dr. King addressed a number of recent developments in interventional cardiology and rated their chances of significantly improving outcomes in patients with stable ischemic heart disease. He graded the innovations’ potential with use of a four-bar schema, akin to the WiFi signal power rating on a cell phone.
 

Noninvasive diagnostics to assess anatomy and physiology

“I think coronary CT angiography [CTA] will become the new diagnostic angiogram,” he predicted. “CTA has gotten much better. Outside the United States, in Europe and particularly in Japan and increasingly in China, CTA is becoming extremely common.”

Dr. King cited a recent multicenter study of blinded heart team treatment decision making on the basis of either CTA or conventional invasive angiography in 223 patients with left main or triple-vessel coronary artery disease (CAD). The level of agreement was impressively high: Coronary artery bypass grafting (CABG) was recommended for 28% of patients on the basis of CTA and 26% with conventional angiography, which suggests the feasibility of treatment decision making based solely on noninvasive imaging, history, and clinical examination (Eur Heart J. 2018 Nov 1;39[41]:3689-98).

“The other thing I like about the potential for noninvasive imaging to guide our interventions is that it may [replace] the diagnostic angiogram, which has largely become extinct,” the cardiologist continued. “If you think about it, patients are referred for an angiogram, and as far as informed consent is concerned, the patient is told to pack his bags, go off to some other city, get in the cath lab, and take the family because of what they might do to you. They might put stents in you, they might operate on you. We don’t have any idea because we don’t know what you have. And the patient has to buy into this. With CTA, the potential is there for people to actually know what you’re going to do to them before you do it.”

Coronary artery calcium scoring for primary risk assessment has taken on a prominent role in the latest practice guidelines. “I think it’s mostly helpful in getting people out of the system because they don’t have any calcium,” in Dr. King’s view.

PET and MRI will remain secondary noninvasive technologies. They will be used mostly to diagnose microvascular disease, but that’s information that doesn’t have much influence on whether interventional procedures are performed.

Overall, he gave noninvasive diagnostic tools high marks for their potential to improve outcomes in patients with stable ischemic heart disease.

“I give it a pretty robust three bars. Maybe you could give it four,” he said.
 

New pharmacologic therapies

Citing in particular the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and the sodium-glucose cotransporter 2 (SGLT2) inhibitors, Dr. King declared, “It may be that the biggest, newest device in interventional cardiology going forward is not a device at all, it’s medical therapy.”

Interventional cardiologists either need to become expert in advanced medical therapies or else have access to someone in their group who prescribes those medications deftly.

“The future care of our patients will require more than percutaneous coronary intervention,” he emphasized.

So, four bars for the new medical therapies.
 

PCI and coronary artery bypass surgery

Both get one bar.

“PCI will be a partner of advanced antiatherosclerotic therapies, but will not be replaced by limiting antianginal therapy to medical treatment only,” Dr. King predicted.

Regarding CABG, he highlighted a recent systematic review and pooled analysis of 11,518 patients with stable ischemic heart disease randomized to CABG or PCI using drug-eluting or bare-metal stents in 11 clinical trials. CABG demonstrated a significant mortality benefit over PCI in patients with multivessel disease, particularly among those with diabetes or a higher degree of coronary disease complexity. However, there was no benefit in terms of 5-year all-cause mortality for CABG over PCI in those with left main disease (Lancet. 2018 Mar 10;391[10124]:9399-48).

“CABG will not go away. I predict that about 25% of revascularizations will continue to be done by surgery,” the cardiologist said. “For patients who can have complete revascularization by PCI, it’ll be done with advanced technology, but probably only by a subset of operators. We have a huge number of interventional cardiologists in this country, and some of them do a lot of these kinds of cases and some don’t.”
 

Endovascular imaging to optimize stent deployment and characterize plaque

Studies suggest that the use of intravascular ultrasound and other endovascular imaging technologies ends up providing better results than when they’re not employed.

“We see greatly increased use of IVUS [intravascular ultrasound], and not so much of optical coherence tomography, because of technical problems. So I give this at least two bars as far as moving practice forward,” according to Dr. King.
 

Bioresorbable scaffolds

This technology, which he noted “was supposed to solve all of our problems,” has tripped and fallen because of its associated increased risk of scaffold thrombosis. He cited a recent network meta-analysis of 91 randomized, controlled trials comparing bioresorbable scaffolds to current-generation metallic drug-eluting stents in more than 105,000 patients. The bioresorbable scaffolds had a significantly higher rate of scaffold thrombosis in the first 30 days after implantation, as well as from 31 days through 1 year and also beyond 1 year. In fact, there was a rising trend for scaffold thrombosis in the bioresorbable device group after the 1 year mark through a mean 3.7 years of follow-up (EuroIntervention. 2018 Mar 20;13[16]:1904-13).

“The overall impact of bioresorbable scaffolds has been nil. We don’t have them. Bioresorbable scaffolds may become noninferior to the best metal stents, but to become mainstream, they should show superiority,” the cardiologist said.

One bar, based on the uncertain possibility that new bioresorbable scaffolds now in early stages of development ultimately pan out.
 

Future training needs

PCI operator volumes are low, and that raises a host of issues regarding future training needs. Should fewer interventionalists be trained? Should training in endovascular imaging be a mandatory part of PCI training? Should interventional cardiology be divided into distinct coronary, structural heart, and peripheral vascular subspecialty domains involving different people, a change that is already informally underway in many places? How are operators who are interested in becoming experts in PCI for chronic total occlusion, diffuse disease, left main disease, or other complex cases going to get enough experience to be able to concentrate in those areas?

These are questions that will need to be addressed in the coming years. The answers will surely affect the delivery of interventional cardiology care.

Dr. King reported having no financial conflicts regarding his presentation.

bjancin@mdedge.com

SOURCE: King SB.

SNOWMASS, COLO. – When Spencer B. King III, MD, shared his thoughts about the future of interventional cardiology at the Annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology, he felt compelled to offer a cautionary note about his past accuracy as a prognosticator.

Bruce Jancin/MDedge News

It was way back at a poster session during the 1976 annual meeting of the American Heart Association in Miami Beach that he first met Andreas Gruentzig, MD, the father of percutaneous coronary intervention (PCI), who was presenting his initial revolutionary work on what he called “coronary transluminal angioplasty” in dogs.

“I looked at the poster and told him it would never work,” recalled Dr. King, professor emeritus of medicine at Emory University in Atlanta.

He soon changed his mind, however, because, to great acclaim, Dr. Gruentzig performed his successful first in-human coronary angioplasty the next year.

He noted that the Snowmass conference has played a significant role in the development of interventional cardiology in the United States. Dr. Gruentzig attended the conference in 1980, and Dr. King and others took that opportunity to persuade him to leave the bureaucratic confines of Zurich and join him at Emory later that year. The two cardiologists worked closely thereafter, refining angioplasty and conducting clinical trials until Dr. Gruentzig’s death in an airplane crash in Georgia in 1985 at age 46 years.

Turning to the future, Dr. King addressed a number of recent developments in interventional cardiology and rated their chances of significantly improving outcomes in patients with stable ischemic heart disease. He graded the innovations’ potential with use of a four-bar schema, akin to the WiFi signal power rating on a cell phone.
 

Noninvasive diagnostics to assess anatomy and physiology

“I think coronary CT angiography [CTA] will become the new diagnostic angiogram,” he predicted. “CTA has gotten much better. Outside the United States, in Europe and particularly in Japan and increasingly in China, CTA is becoming extremely common.”

Dr. King cited a recent multicenter study of blinded heart team treatment decision making on the basis of either CTA or conventional invasive angiography in 223 patients with left main or triple-vessel coronary artery disease (CAD). The level of agreement was impressively high: Coronary artery bypass grafting (CABG) was recommended for 28% of patients on the basis of CTA and 26% with conventional angiography, which suggests the feasibility of treatment decision making based solely on noninvasive imaging, history, and clinical examination (Eur Heart J. 2018 Nov 1;39[41]:3689-98).

“The other thing I like about the potential for noninvasive imaging to guide our interventions is that it may [replace] the diagnostic angiogram, which has largely become extinct,” the cardiologist continued. “If you think about it, patients are referred for an angiogram, and as far as informed consent is concerned, the patient is told to pack his bags, go off to some other city, get in the cath lab, and take the family because of what they might do to you. They might put stents in you, they might operate on you. We don’t have any idea because we don’t know what you have. And the patient has to buy into this. With CTA, the potential is there for people to actually know what you’re going to do to them before you do it.”

Coronary artery calcium scoring for primary risk assessment has taken on a prominent role in the latest practice guidelines. “I think it’s mostly helpful in getting people out of the system because they don’t have any calcium,” in Dr. King’s view.

PET and MRI will remain secondary noninvasive technologies. They will be used mostly to diagnose microvascular disease, but that’s information that doesn’t have much influence on whether interventional procedures are performed.

Overall, he gave noninvasive diagnostic tools high marks for their potential to improve outcomes in patients with stable ischemic heart disease.

“I give it a pretty robust three bars. Maybe you could give it four,” he said.
 

New pharmacologic therapies

Citing in particular the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and the sodium-glucose cotransporter 2 (SGLT2) inhibitors, Dr. King declared, “It may be that the biggest, newest device in interventional cardiology going forward is not a device at all, it’s medical therapy.”

Interventional cardiologists either need to become expert in advanced medical therapies or else have access to someone in their group who prescribes those medications deftly.

“The future care of our patients will require more than percutaneous coronary intervention,” he emphasized.

So, four bars for the new medical therapies.
 

PCI and coronary artery bypass surgery

Both get one bar.

“PCI will be a partner of advanced antiatherosclerotic therapies, but will not be replaced by limiting antianginal therapy to medical treatment only,” Dr. King predicted.

Regarding CABG, he highlighted a recent systematic review and pooled analysis of 11,518 patients with stable ischemic heart disease randomized to CABG or PCI using drug-eluting or bare-metal stents in 11 clinical trials. CABG demonstrated a significant mortality benefit over PCI in patients with multivessel disease, particularly among those with diabetes or a higher degree of coronary disease complexity. However, there was no benefit in terms of 5-year all-cause mortality for CABG over PCI in those with left main disease (Lancet. 2018 Mar 10;391[10124]:9399-48).

“CABG will not go away. I predict that about 25% of revascularizations will continue to be done by surgery,” the cardiologist said. “For patients who can have complete revascularization by PCI, it’ll be done with advanced technology, but probably only by a subset of operators. We have a huge number of interventional cardiologists in this country, and some of them do a lot of these kinds of cases and some don’t.”
 

Endovascular imaging to optimize stent deployment and characterize plaque

Studies suggest that the use of intravascular ultrasound and other endovascular imaging technologies ends up providing better results than when they’re not employed.

“We see greatly increased use of IVUS [intravascular ultrasound], and not so much of optical coherence tomography, because of technical problems. So I give this at least two bars as far as moving practice forward,” according to Dr. King.
 

Bioresorbable scaffolds

This technology, which he noted “was supposed to solve all of our problems,” has tripped and fallen because of its associated increased risk of scaffold thrombosis. He cited a recent network meta-analysis of 91 randomized, controlled trials comparing bioresorbable scaffolds to current-generation metallic drug-eluting stents in more than 105,000 patients. The bioresorbable scaffolds had a significantly higher rate of scaffold thrombosis in the first 30 days after implantation, as well as from 31 days through 1 year and also beyond 1 year. In fact, there was a rising trend for scaffold thrombosis in the bioresorbable device group after the 1 year mark through a mean 3.7 years of follow-up (EuroIntervention. 2018 Mar 20;13[16]:1904-13).

“The overall impact of bioresorbable scaffolds has been nil. We don’t have them. Bioresorbable scaffolds may become noninferior to the best metal stents, but to become mainstream, they should show superiority,” the cardiologist said.

One bar, based on the uncertain possibility that new bioresorbable scaffolds now in early stages of development ultimately pan out.
 

Future training needs

PCI operator volumes are low, and that raises a host of issues regarding future training needs. Should fewer interventionalists be trained? Should training in endovascular imaging be a mandatory part of PCI training? Should interventional cardiology be divided into distinct coronary, structural heart, and peripheral vascular subspecialty domains involving different people, a change that is already informally underway in many places? How are operators who are interested in becoming experts in PCI for chronic total occlusion, diffuse disease, left main disease, or other complex cases going to get enough experience to be able to concentrate in those areas?

These are questions that will need to be addressed in the coming years. The answers will surely affect the delivery of interventional cardiology care.

Dr. King reported having no financial conflicts regarding his presentation.

bjancin@mdedge.com

SOURCE: King SB.

SNOWMASS, COLO. – When Spencer B. King III, MD, shared his thoughts about the future of interventional cardiology at the Annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology, he felt compelled to offer a cautionary note about his past accuracy as a prognosticator.

Bruce Jancin/MDedge News

It was way back at a poster session during the 1976 annual meeting of the American Heart Association in Miami Beach that he first met Andreas Gruentzig, MD, the father of percutaneous coronary intervention (PCI), who was presenting his initial revolutionary work on what he called “coronary transluminal angioplasty” in dogs.

“I looked at the poster and told him it would never work,” recalled Dr. King, professor emeritus of medicine at Emory University in Atlanta.

He soon changed his mind, however, because, to great acclaim, Dr. Gruentzig performed his successful first in-human coronary angioplasty the next year.

He noted that the Snowmass conference has played a significant role in the development of interventional cardiology in the United States. Dr. Gruentzig attended the conference in 1980, and Dr. King and others took that opportunity to persuade him to leave the bureaucratic confines of Zurich and join him at Emory later that year. The two cardiologists worked closely thereafter, refining angioplasty and conducting clinical trials until Dr. Gruentzig’s death in an airplane crash in Georgia in 1985 at age 46 years.

Turning to the future, Dr. King addressed a number of recent developments in interventional cardiology and rated their chances of significantly improving outcomes in patients with stable ischemic heart disease. He graded the innovations’ potential with use of a four-bar schema, akin to the WiFi signal power rating on a cell phone.
 

Noninvasive diagnostics to assess anatomy and physiology

“I think coronary CT angiography [CTA] will become the new diagnostic angiogram,” he predicted. “CTA has gotten much better. Outside the United States, in Europe and particularly in Japan and increasingly in China, CTA is becoming extremely common.”

Dr. King cited a recent multicenter study of blinded heart team treatment decision making on the basis of either CTA or conventional invasive angiography in 223 patients with left main or triple-vessel coronary artery disease (CAD). The level of agreement was impressively high: Coronary artery bypass grafting (CABG) was recommended for 28% of patients on the basis of CTA and 26% with conventional angiography, which suggests the feasibility of treatment decision making based solely on noninvasive imaging, history, and clinical examination (Eur Heart J. 2018 Nov 1;39[41]:3689-98).

“The other thing I like about the potential for noninvasive imaging to guide our interventions is that it may [replace] the diagnostic angiogram, which has largely become extinct,” the cardiologist continued. “If you think about it, patients are referred for an angiogram, and as far as informed consent is concerned, the patient is told to pack his bags, go off to some other city, get in the cath lab, and take the family because of what they might do to you. They might put stents in you, they might operate on you. We don’t have any idea because we don’t know what you have. And the patient has to buy into this. With CTA, the potential is there for people to actually know what you’re going to do to them before you do it.”

Coronary artery calcium scoring for primary risk assessment has taken on a prominent role in the latest practice guidelines. “I think it’s mostly helpful in getting people out of the system because they don’t have any calcium,” in Dr. King’s view.

PET and MRI will remain secondary noninvasive technologies. They will be used mostly to diagnose microvascular disease, but that’s information that doesn’t have much influence on whether interventional procedures are performed.

Overall, he gave noninvasive diagnostic tools high marks for their potential to improve outcomes in patients with stable ischemic heart disease.

“I give it a pretty robust three bars. Maybe you could give it four,” he said.
 

New pharmacologic therapies

Citing in particular the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and the sodium-glucose cotransporter 2 (SGLT2) inhibitors, Dr. King declared, “It may be that the biggest, newest device in interventional cardiology going forward is not a device at all, it’s medical therapy.”

Interventional cardiologists either need to become expert in advanced medical therapies or else have access to someone in their group who prescribes those medications deftly.

“The future care of our patients will require more than percutaneous coronary intervention,” he emphasized.

So, four bars for the new medical therapies.
 

PCI and coronary artery bypass surgery

Both get one bar.

“PCI will be a partner of advanced antiatherosclerotic therapies, but will not be replaced by limiting antianginal therapy to medical treatment only,” Dr. King predicted.

Regarding CABG, he highlighted a recent systematic review and pooled analysis of 11,518 patients with stable ischemic heart disease randomized to CABG or PCI using drug-eluting or bare-metal stents in 11 clinical trials. CABG demonstrated a significant mortality benefit over PCI in patients with multivessel disease, particularly among those with diabetes or a higher degree of coronary disease complexity. However, there was no benefit in terms of 5-year all-cause mortality for CABG over PCI in those with left main disease (Lancet. 2018 Mar 10;391[10124]:9399-48).

“CABG will not go away. I predict that about 25% of revascularizations will continue to be done by surgery,” the cardiologist said. “For patients who can have complete revascularization by PCI, it’ll be done with advanced technology, but probably only by a subset of operators. We have a huge number of interventional cardiologists in this country, and some of them do a lot of these kinds of cases and some don’t.”
 

Endovascular imaging to optimize stent deployment and characterize plaque

Studies suggest that the use of intravascular ultrasound and other endovascular imaging technologies ends up providing better results than when they’re not employed.

“We see greatly increased use of IVUS [intravascular ultrasound], and not so much of optical coherence tomography, because of technical problems. So I give this at least two bars as far as moving practice forward,” according to Dr. King.
 

Bioresorbable scaffolds

This technology, which he noted “was supposed to solve all of our problems,” has tripped and fallen because of its associated increased risk of scaffold thrombosis. He cited a recent network meta-analysis of 91 randomized, controlled trials comparing bioresorbable scaffolds to current-generation metallic drug-eluting stents in more than 105,000 patients. The bioresorbable scaffolds had a significantly higher rate of scaffold thrombosis in the first 30 days after implantation, as well as from 31 days through 1 year and also beyond 1 year. In fact, there was a rising trend for scaffold thrombosis in the bioresorbable device group after the 1 year mark through a mean 3.7 years of follow-up (EuroIntervention. 2018 Mar 20;13[16]:1904-13).

“The overall impact of bioresorbable scaffolds has been nil. We don’t have them. Bioresorbable scaffolds may become noninferior to the best metal stents, but to become mainstream, they should show superiority,” the cardiologist said.

One bar, based on the uncertain possibility that new bioresorbable scaffolds now in early stages of development ultimately pan out.
 

Future training needs

PCI operator volumes are low, and that raises a host of issues regarding future training needs. Should fewer interventionalists be trained? Should training in endovascular imaging be a mandatory part of PCI training? Should interventional cardiology be divided into distinct coronary, structural heart, and peripheral vascular subspecialty domains involving different people, a change that is already informally underway in many places? How are operators who are interested in becoming experts in PCI for chronic total occlusion, diffuse disease, left main disease, or other complex cases going to get enough experience to be able to concentrate in those areas?

These are questions that will need to be addressed in the coming years. The answers will surely affect the delivery of interventional cardiology care.

Dr. King reported having no financial conflicts regarding his presentation.

bjancin@mdedge.com

SOURCE: King SB.

Reducing fear and anxiety in children undergoing dermatologic procedures is possible with techniques based on cognitive behavioral therapy, according to a report published in Pediatric Dermatology.

fotostorm/Getty Images

For many children, the anticipation of pain and the anxiety about a procedure results in a more painful experience, wrote Andrew M. Armenta of the University of Texas, Galveston, and his colleagues. Preparing children in advance and using cognitive behavioral therapy (CBT) strategies in the moment can help reduce their anxiety.

“CBT is a skill‐based approach that focuses on the present and aims to teach efficient ways of identifying distorted thinking, modifying beliefs, and changing behaviors for a more favorable outcome of real‐life situations,” they wrote.

First, Dr. Armenta and his associates advised, be honest with children about what to expect from a procedure. Evidence does not support phrases such as, “It won’t hurt,” or “It will be over soon,” to reduce anxiety.

Timing the disclosure of a procedure and creating the appropriate setting also can help reduce anxiety. For very young children, short notice of a procedure is often best, with the promise of a small reward or outing afterward. Older children may want some advance notice so they can feel prepared, but their specific concerns should be addressed.

CBT-based techniques include deep breathing and positive coping statements such as “I can do this” for older children, or encouraging them to talk about a family pet or listen to music. Younger children may be distracted with pinwheels, rattles, or songs. “Additionally, in recent years, virtual reality headsets have even proved to be effective distractors, resulting in an overall reduction in both pain and fear,” Dr. Armenta and his associates noted.

Other useful strategies include allowing children to choose their position and location for an injection or procedure when possible. Small children may be able to sit on the lap of an adult, and older children may prefer sitting up to lying down. Avoid physical restraint unless it is absolutely necessary for safety, the researchers emphasized.

Incorporating CBT-based strategies of breathing and distraction with honesty and respectful disclosure of what is being done and why “not only makes practicing pediatric dermatology easier, but also can improve patient adherence to painful procedures,” they said.

No disclosure information was given.

SOURCE: Armenta AM et al. Pediatr Dermatol. 2019. doi: 10.1111/pde.13739.

Reducing fear and anxiety in children undergoing dermatologic procedures is possible with techniques based on cognitive behavioral therapy, according to a report published in Pediatric Dermatology.

fotostorm/Getty Images

For many children, the anticipation of pain and the anxiety about a procedure results in a more painful experience, wrote Andrew M. Armenta of the University of Texas, Galveston, and his colleagues. Preparing children in advance and using cognitive behavioral therapy (CBT) strategies in the moment can help reduce their anxiety.

“CBT is a skill‐based approach that focuses on the present and aims to teach efficient ways of identifying distorted thinking, modifying beliefs, and changing behaviors for a more favorable outcome of real‐life situations,” they wrote.

First, Dr. Armenta and his associates advised, be honest with children about what to expect from a procedure. Evidence does not support phrases such as, “It won’t hurt,” or “It will be over soon,” to reduce anxiety.

Timing the disclosure of a procedure and creating the appropriate setting also can help reduce anxiety. For very young children, short notice of a procedure is often best, with the promise of a small reward or outing afterward. Older children may want some advance notice so they can feel prepared, but their specific concerns should be addressed.

CBT-based techniques include deep breathing and positive coping statements such as “I can do this” for older children, or encouraging them to talk about a family pet or listen to music. Younger children may be distracted with pinwheels, rattles, or songs. “Additionally, in recent years, virtual reality headsets have even proved to be effective distractors, resulting in an overall reduction in both pain and fear,” Dr. Armenta and his associates noted.

Other useful strategies include allowing children to choose their position and location for an injection or procedure when possible. Small children may be able to sit on the lap of an adult, and older children may prefer sitting up to lying down. Avoid physical restraint unless it is absolutely necessary for safety, the researchers emphasized.

Incorporating CBT-based strategies of breathing and distraction with honesty and respectful disclosure of what is being done and why “not only makes practicing pediatric dermatology easier, but also can improve patient adherence to painful procedures,” they said.

No disclosure information was given.

SOURCE: Armenta AM et al. Pediatr Dermatol. 2019. doi: 10.1111/pde.13739.

Reducing fear and anxiety in children undergoing dermatologic procedures is possible with techniques based on cognitive behavioral therapy, according to a report published in Pediatric Dermatology.

fotostorm/Getty Images

For many children, the anticipation of pain and the anxiety about a procedure results in a more painful experience, wrote Andrew M. Armenta of the University of Texas, Galveston, and his colleagues. Preparing children in advance and using cognitive behavioral therapy (CBT) strategies in the moment can help reduce their anxiety.

“CBT is a skill‐based approach that focuses on the present and aims to teach efficient ways of identifying distorted thinking, modifying beliefs, and changing behaviors for a more favorable outcome of real‐life situations,” they wrote.

First, Dr. Armenta and his associates advised, be honest with children about what to expect from a procedure. Evidence does not support phrases such as, “It won’t hurt,” or “It will be over soon,” to reduce anxiety.

Timing the disclosure of a procedure and creating the appropriate setting also can help reduce anxiety. For very young children, short notice of a procedure is often best, with the promise of a small reward or outing afterward. Older children may want some advance notice so they can feel prepared, but their specific concerns should be addressed.

CBT-based techniques include deep breathing and positive coping statements such as “I can do this” for older children, or encouraging them to talk about a family pet or listen to music. Younger children may be distracted with pinwheels, rattles, or songs. “Additionally, in recent years, virtual reality headsets have even proved to be effective distractors, resulting in an overall reduction in both pain and fear,” Dr. Armenta and his associates noted.

Other useful strategies include allowing children to choose their position and location for an injection or procedure when possible. Small children may be able to sit on the lap of an adult, and older children may prefer sitting up to lying down. Avoid physical restraint unless it is absolutely necessary for safety, the researchers emphasized.

Incorporating CBT-based strategies of breathing and distraction with honesty and respectful disclosure of what is being done and why “not only makes practicing pediatric dermatology easier, but also can improve patient adherence to painful procedures,” they said.

No disclosure information was given.

SOURCE: Armenta AM et al. Pediatr Dermatol. 2019. doi: 10.1111/pde.13739.

You may have noticed that one of topics I like to write about in this column is the assault on the practice of medicine: the obligations that steal our time from patients without either the value or outcomes our patients see. It is these extraneous demands on our time and on our psyches that dehumanize medical practice as experienced by our patients and contribute to physician burnout. High on my list is the requirement for prior authorization for medications.

In 2015, I wrote a column, “Prior Authorization for Medications: Who oversees placement of the hoops?” The article followed my unsuccessful 6-week-long endeavor to get modafinil authorized for a patient. My efforts included interactions with the insurance company’s chief medical officer, the insurance commissioners in three states, my U.S. senator, and finally, the American Psychiatric Association’s attorney, Colleen Coyle, who has been working on this issue along with the American Medical Association and other medical specialty organizations for years now. The irony of the article is that, after it came out, a reader informed me that modafinil could be obtained from Costco for $34 for 30 pills, while every pharmacy I had checked was selling the generic medication for nearly $1,000 for the same number of pills!

One might make the case that prior authorization saves money by rationing the most expensive medications. And I might counter that physicians should be willing to try less expensive medications first – if we only knew the price of the medications we are prescribing. There is, however, no clear logic to the tremendous variability in price across pharmacies, which can amount to hundreds of dollars a month in the cost to an uninsured patient, and none of which reflects what might be a negotiated cost for those using health insurance. The newest medications are expensive from any retailer, but when it comes to older generics, it’s a crapshoot.

Years have passed since my prior authorization fiasco. Today, I keep a GoodRx app on my phone and often reference it when prescribing medications that might be expensive at one pharmacy but not at another. The app tells me that I can now buy 30 pills of the modafinil for $40.34 at grocery store pharmacy that is 2.7 miles from my office or for $305.50 at Walgreens, 3.6 miles away. A quick call to Costco shows that the price there has gone up to $40.89. For the prescriptions that I have written since that article, I have told patients that their insurance providers may not authorize the medication and if that is the case, they should price shop, as I don’t have the tenacity to go through the prior authorization process I endured in 2015.

So what progress has the APA made over the past 4 years? I wrote back to the APA’s attorney, Ms. Coyle, to ask for an update. Ms. Coyle was kind enough to respond in some detail. It was heartening to hear that in many states, my own state of Maryland included, prior authorization is no longer allowed for medications used to treat opiate addictions, and there is one less obstacle to obtaining care for a growing number of patients during our overdose epidemic.

Other news, however, is not all good. Medicare plans to increase the use of prior authorization.

Ms. Coyle provided data that confirmed what most physicians suspected. “The AMA did a survey¹ and found 92% of physicians report that ‘prior authorizations programs have a negative impact on patient clinical outcomes.’ The AMA study revealed that ‘every week a medical practice completes an average of 29.1 prior authorization requirements per physician, which takes an average of 14.6 hours to process – the equivalent of nearly two business days.’ ”

She recounted the efforts the APA has made on behalf of psychiatrists. “We are working with the AMA and other physician groups to address the issue and recommended [Health and Human Services] address the burden of prior authorization as part of its Patients over Paperwork Initiative.² Through our website and the helpline, we collected stories from our members about the burden it causes and the negative impact it has on patient care. We’ve shared the stories with the American Medical Association to use in joint advocacy efforts with the administration and private insurers.”

Finally, the APA has written a letter to the Centers for Medicare & Medicaid Services in opposition to a proposal for increased utilization review of Medicare Part D protected classes medications, which include antipsychotics and antidepressants. “We strongly oppose the proposal,” Ms. Coyle noted, “and asked our district branches to also submit letters in opposition.”

What can individual psychiatrists do to advocate? I noted that many of my efforts were futile. My U.S. senator responded with a letter that said my problem was not in his domain.

“As for the best way to approach the issue in the state, we recommend working with the state medical society to push for legislation. The AMA has draft legislation that may be used. It would also be helpful to collect the stories from the members about their challenges with prior authorization and impact on patient care/outcomes to share with state legislatures. It may also be beneficial to share these concerns with the state insurance commissioner and Department of Health and Human Services,” Ms. Coyle wrote. She noted it would be helpful for members to work directly with the district branches of the APA.

I am still left with some sense of futility. In 2014, Danielle Ofri, MD, PhD, a physician and writer, wrote an op-ed³ for the New York Times, “Adventures in ‘Prior Authorization,’ ” where she detailed the egregious practice. In the past 5 years, not much has changed, and insurers have not taken to the idea that preserving physician time for clinical care and face-to-face interactions with patients is the priority that we all might like it to be.

Dr. Miller is the coauthor with Annette Hanson, MD, of “Committed: The Battle Over Involuntary Psychiatric Care” (Baltimore: Johns Hopkins University Press, 2016). She has a private practice in Baltimore.

References

1. AMA Prior Authorization Physician Survey, 2017.

2. CMS Patients Over Paperwork Initiative, CMS.gov.

3. New York Times, Aug. 3, 2014.

You may have noticed that one of topics I like to write about in this column is the assault on the practice of medicine: the obligations that steal our time from patients without either the value or outcomes our patients see. It is these extraneous demands on our time and on our psyches that dehumanize medical practice as experienced by our patients and contribute to physician burnout. High on my list is the requirement for prior authorization for medications.

In 2015, I wrote a column, “Prior Authorization for Medications: Who oversees placement of the hoops?” The article followed my unsuccessful 6-week-long endeavor to get modafinil authorized for a patient. My efforts included interactions with the insurance company’s chief medical officer, the insurance commissioners in three states, my U.S. senator, and finally, the American Psychiatric Association’s attorney, Colleen Coyle, who has been working on this issue along with the American Medical Association and other medical specialty organizations for years now. The irony of the article is that, after it came out, a reader informed me that modafinil could be obtained from Costco for $34 for 30 pills, while every pharmacy I had checked was selling the generic medication for nearly $1,000 for the same number of pills!

One might make the case that prior authorization saves money by rationing the most expensive medications. And I might counter that physicians should be willing to try less expensive medications first – if we only knew the price of the medications we are prescribing. There is, however, no clear logic to the tremendous variability in price across pharmacies, which can amount to hundreds of dollars a month in the cost to an uninsured patient, and none of which reflects what might be a negotiated cost for those using health insurance. The newest medications are expensive from any retailer, but when it comes to older generics, it’s a crapshoot.

Years have passed since my prior authorization fiasco. Today, I keep a GoodRx app on my phone and often reference it when prescribing medications that might be expensive at one pharmacy but not at another. The app tells me that I can now buy 30 pills of the modafinil for $40.34 at grocery store pharmacy that is 2.7 miles from my office or for $305.50 at Walgreens, 3.6 miles away. A quick call to Costco shows that the price there has gone up to $40.89. For the prescriptions that I have written since that article, I have told patients that their insurance providers may not authorize the medication and if that is the case, they should price shop, as I don’t have the tenacity to go through the prior authorization process I endured in 2015.

So what progress has the APA made over the past 4 years? I wrote back to the APA’s attorney, Ms. Coyle, to ask for an update. Ms. Coyle was kind enough to respond in some detail. It was heartening to hear that in many states, my own state of Maryland included, prior authorization is no longer allowed for medications used to treat opiate addictions, and there is one less obstacle to obtaining care for a growing number of patients during our overdose epidemic.

Other news, however, is not all good. Medicare plans to increase the use of prior authorization.

Ms. Coyle provided data that confirmed what most physicians suspected. “The AMA did a survey¹ and found 92% of physicians report that ‘prior authorizations programs have a negative impact on patient clinical outcomes.’ The AMA study revealed that ‘every week a medical practice completes an average of 29.1 prior authorization requirements per physician, which takes an average of 14.6 hours to process – the equivalent of nearly two business days.’ ”

She recounted the efforts the APA has made on behalf of psychiatrists. “We are working with the AMA and other physician groups to address the issue and recommended [Health and Human Services] address the burden of prior authorization as part of its Patients over Paperwork Initiative.² Through our website and the helpline, we collected stories from our members about the burden it causes and the negative impact it has on patient care. We’ve shared the stories with the American Medical Association to use in joint advocacy efforts with the administration and private insurers.”

Finally, the APA has written a letter to the Centers for Medicare & Medicaid Services in opposition to a proposal for increased utilization review of Medicare Part D protected classes medications, which include antipsychotics and antidepressants. “We strongly oppose the proposal,” Ms. Coyle noted, “and asked our district branches to also submit letters in opposition.”

What can individual psychiatrists do to advocate? I noted that many of my efforts were futile. My U.S. senator responded with a letter that said my problem was not in his domain.

“As for the best way to approach the issue in the state, we recommend working with the state medical society to push for legislation. The AMA has draft legislation that may be used. It would also be helpful to collect the stories from the members about their challenges with prior authorization and impact on patient care/outcomes to share with state legislatures. It may also be beneficial to share these concerns with the state insurance commissioner and Department of Health and Human Services,” Ms. Coyle wrote. She noted it would be helpful for members to work directly with the district branches of the APA.

I am still left with some sense of futility. In 2014, Danielle Ofri, MD, PhD, a physician and writer, wrote an op-ed³ for the New York Times, “Adventures in ‘Prior Authorization,’ ” where she detailed the egregious practice. In the past 5 years, not much has changed, and insurers have not taken to the idea that preserving physician time for clinical care and face-to-face interactions with patients is the priority that we all might like it to be.

Dr. Miller is the coauthor with Annette Hanson, MD, of “Committed: The Battle Over Involuntary Psychiatric Care” (Baltimore: Johns Hopkins University Press, 2016). She has a private practice in Baltimore.

References

1. AMA Prior Authorization Physician Survey, 2017.

2. CMS Patients Over Paperwork Initiative, CMS.gov.

3. New York Times, Aug. 3, 2014.

You may have noticed that one of topics I like to write about in this column is the assault on the practice of medicine: the obligations that steal our time from patients without either the value or outcomes our patients see. It is these extraneous demands on our time and on our psyches that dehumanize medical practice as experienced by our patients and contribute to physician burnout. High on my list is the requirement for prior authorization for medications.

In 2015, I wrote a column, “Prior Authorization for Medications: Who oversees placement of the hoops?” The article followed my unsuccessful 6-week-long endeavor to get modafinil authorized for a patient. My efforts included interactions with the insurance company’s chief medical officer, the insurance commissioners in three states, my U.S. senator, and finally, the American Psychiatric Association’s attorney, Colleen Coyle, who has been working on this issue along with the American Medical Association and other medical specialty organizations for years now. The irony of the article is that, after it came out, a reader informed me that modafinil could be obtained from Costco for $34 for 30 pills, while every pharmacy I had checked was selling the generic medication for nearly $1,000 for the same number of pills!

One might make the case that prior authorization saves money by rationing the most expensive medications. And I might counter that physicians should be willing to try less expensive medications first – if we only knew the price of the medications we are prescribing. There is, however, no clear logic to the tremendous variability in price across pharmacies, which can amount to hundreds of dollars a month in the cost to an uninsured patient, and none of which reflects what might be a negotiated cost for those using health insurance. The newest medications are expensive from any retailer, but when it comes to older generics, it’s a crapshoot.

Years have passed since my prior authorization fiasco. Today, I keep a GoodRx app on my phone and often reference it when prescribing medications that might be expensive at one pharmacy but not at another. The app tells me that I can now buy 30 pills of the modafinil for $40.34 at grocery store pharmacy that is 2.7 miles from my office or for $305.50 at Walgreens, 3.6 miles away. A quick call to Costco shows that the price there has gone up to $40.89. For the prescriptions that I have written since that article, I have told patients that their insurance providers may not authorize the medication and if that is the case, they should price shop, as I don’t have the tenacity to go through the prior authorization process I endured in 2015.

So what progress has the APA made over the past 4 years? I wrote back to the APA’s attorney, Ms. Coyle, to ask for an update. Ms. Coyle was kind enough to respond in some detail. It was heartening to hear that in many states, my own state of Maryland included, prior authorization is no longer allowed for medications used to treat opiate addictions, and there is one less obstacle to obtaining care for a growing number of patients during our overdose epidemic.

Other news, however, is not all good. Medicare plans to increase the use of prior authorization.

Ms. Coyle provided data that confirmed what most physicians suspected. “The AMA did a survey¹ and found 92% of physicians report that ‘prior authorizations programs have a negative impact on patient clinical outcomes.’ The AMA study revealed that ‘every week a medical practice completes an average of 29.1 prior authorization requirements per physician, which takes an average of 14.6 hours to process – the equivalent of nearly two business days.’ ”

She recounted the efforts the APA has made on behalf of psychiatrists. “We are working with the AMA and other physician groups to address the issue and recommended [Health and Human Services] address the burden of prior authorization as part of its Patients over Paperwork Initiative.² Through our website and the helpline, we collected stories from our members about the burden it causes and the negative impact it has on patient care. We’ve shared the stories with the American Medical Association to use in joint advocacy efforts with the administration and private insurers.”

Finally, the APA has written a letter to the Centers for Medicare & Medicaid Services in opposition to a proposal for increased utilization review of Medicare Part D protected classes medications, which include antipsychotics and antidepressants. “We strongly oppose the proposal,” Ms. Coyle noted, “and asked our district branches to also submit letters in opposition.”

What can individual psychiatrists do to advocate? I noted that many of my efforts were futile. My U.S. senator responded with a letter that said my problem was not in his domain.

“As for the best way to approach the issue in the state, we recommend working with the state medical society to push for legislation. The AMA has draft legislation that may be used. It would also be helpful to collect the stories from the members about their challenges with prior authorization and impact on patient care/outcomes to share with state legislatures. It may also be beneficial to share these concerns with the state insurance commissioner and Department of Health and Human Services,” Ms. Coyle wrote. She noted it would be helpful for members to work directly with the district branches of the APA.

I am still left with some sense of futility. In 2014, Danielle Ofri, MD, PhD, a physician and writer, wrote an op-ed³ for the New York Times, “Adventures in ‘Prior Authorization,’ ” where she detailed the egregious practice. In the past 5 years, not much has changed, and insurers have not taken to the idea that preserving physician time for clinical care and face-to-face interactions with patients is the priority that we all might like it to be.

Dr. Miller is the coauthor with Annette Hanson, MD, of “Committed: The Battle Over Involuntary Psychiatric Care” (Baltimore: Johns Hopkins University Press, 2016). She has a private practice in Baltimore.

References

1. AMA Prior Authorization Physician Survey, 2017.

2. CMS Patients Over Paperwork Initiative, CMS.gov.

3. New York Times, Aug. 3, 2014.

New research suggests guadecitabine may be an option for select patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) who have failed treatment with azacitidine.

National Institutes of Health/Wikimedia Commons/Public Domain

In a phase 2 trial, eight of 56 patients with high-risk MDS or low-blast-count AML responded to guadecitabine after azacitidine failure. Patients were significantly more likely to respond if they had few or no somatic mutations.

Marie Sébert, MD, of Hôpital Saint Louis in Paris and her colleagues conducted this trial and reported the results in Haematologica.

The trial (NCT02197676) included 56 patients with the following disease types:

• Refractory anemia with excess blasts (RAEB) type 2 (n = 31; 55%).
• RAEB type 1 (n = 11; 20%).
• Low-blast-count AML (n = 11; 20%).
• Refractory cytopenias with multilineage dysplasia (RCMD; n = 2; 4%).
• Chronic myelomonocytic leukemia (n = 1; 2%).

The patients had a median age of 75 years (range, 70-79) at baseline, and 37 (66%) were men. Thirty-four patients (61%) had very-high-risk disease according to the revised International Prognostic Scoring System. Forty-nine patients (87.5%) had at least one somatic mutation. The most commonly mutated genes were ASXL1, RUNX1, TP53, U2AF1, and DNMT3A.

Most patients (n = 41, 73%) had relapsed after azacitidine, and 15 (27%) had primary resistance to the drug. Patients had received a median of 13 azacitidine cycles (range, 6-23).

The patients received guadecitabine subcutaneously at 60 mg/m² on days 1-5 of a 28-day cycle. They were treated until progression, death, unacceptable toxicity, or no response after six to nine cycles. Patients received a median of three cycles (range, 0-27). One patient died of infection before receiving guadecitabine, but the remaining 55 patients received at least one cycle of treatment. Eighteen patients had a dose reduction.

Eight patients (14.3%) responded to guadecitabine. Two patients achieved a complete response (CR) – one who had RAEB-2 and one with AML. Two patients with RAEB-1 had marrow CRs. Two patients – one with RAEB-2 and one with AML – had marrow CRs with hematologic improvement. A patient with RCMD had hematologic improvement, and a patient with RAEB-2 had a partial response.

The researchers said mutation frequency was the only significant predictor of response. The response rate was significantly higher in patients who did not have somatic mutations (P = .036). The median number of mutations was one (range, zero to three) in responders and two (range, zero to six) in nonresponders (P = .035). None of the patients with TP53 mutations achieved a response.

The median duration of response was 11.5 months. The median overall survival was 17.9 months in responders and 7.1 months in the overall population.

In a multivariate analysis, the following factors were significantly associated with longer survival:
 

• Having low- to high-risk (vs. very-high-risk) disease (P = .03).
• Having experienced primary (vs. secondary) azacitidine failure (P = .01).
• Having a high rate of demethylation in blood during the first treatment cycle (P = .03).

There were 99 serious adverse events (AEs) reported in 44 patients. Most AEs were hematologic events, and the most common of these was myelosuppression (n = 88; 88%). The most common grade 3/4 nonhematologic AE was pulmonary toxicity (n = 7; 12.5%). Thirteen patients were hospitalized for febrile neutropenia for a median of 14 days.

The researchers said patients reported less pain and fewer secondary lesions with guadecitabine than they had with azacitidine.

This trial was sponsored by Groupe Francophone des Myelodysplasies in collaboration with Astex Pharmaceuticals. The researchers reported having no competing interests.

jensmith@mdedge.com

SOURCE: Sébert M et al. Haematologica. 2019 Feb 7. doi: 0.3324/haematol.2018.207118.

New research suggests guadecitabine may be an option for select patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) who have failed treatment with azacitidine.

National Institutes of Health/Wikimedia Commons/Public Domain

In a phase 2 trial, eight of 56 patients with high-risk MDS or low-blast-count AML responded to guadecitabine after azacitidine failure. Patients were significantly more likely to respond if they had few or no somatic mutations.

Marie Sébert, MD, of Hôpital Saint Louis in Paris and her colleagues conducted this trial and reported the results in Haematologica.

The trial (NCT02197676) included 56 patients with the following disease types:

• Refractory anemia with excess blasts (RAEB) type 2 (n = 31; 55%).
• RAEB type 1 (n = 11; 20%).
• Low-blast-count AML (n = 11; 20%).
• Refractory cytopenias with multilineage dysplasia (RCMD; n = 2; 4%).
• Chronic myelomonocytic leukemia (n = 1; 2%).

The patients had a median age of 75 years (range, 70-79) at baseline, and 37 (66%) were men. Thirty-four patients (61%) had very-high-risk disease according to the revised International Prognostic Scoring System. Forty-nine patients (87.5%) had at least one somatic mutation. The most commonly mutated genes were ASXL1, RUNX1, TP53, U2AF1, and DNMT3A.

Most patients (n = 41, 73%) had relapsed after azacitidine, and 15 (27%) had primary resistance to the drug. Patients had received a median of 13 azacitidine cycles (range, 6-23).

The patients received guadecitabine subcutaneously at 60 mg/m² on days 1-5 of a 28-day cycle. They were treated until progression, death, unacceptable toxicity, or no response after six to nine cycles. Patients received a median of three cycles (range, 0-27). One patient died of infection before receiving guadecitabine, but the remaining 55 patients received at least one cycle of treatment. Eighteen patients had a dose reduction.

Eight patients (14.3%) responded to guadecitabine. Two patients achieved a complete response (CR) – one who had RAEB-2 and one with AML. Two patients with RAEB-1 had marrow CRs. Two patients – one with RAEB-2 and one with AML – had marrow CRs with hematologic improvement. A patient with RCMD had hematologic improvement, and a patient with RAEB-2 had a partial response.

The researchers said mutation frequency was the only significant predictor of response. The response rate was significantly higher in patients who did not have somatic mutations (P = .036). The median number of mutations was one (range, zero to three) in responders and two (range, zero to six) in nonresponders (P = .035). None of the patients with TP53 mutations achieved a response.

The median duration of response was 11.5 months. The median overall survival was 17.9 months in responders and 7.1 months in the overall population.

In a multivariate analysis, the following factors were significantly associated with longer survival:
 

• Having low- to high-risk (vs. very-high-risk) disease (P = .03).
• Having experienced primary (vs. secondary) azacitidine failure (P = .01).
• Having a high rate of demethylation in blood during the first treatment cycle (P = .03).

There were 99 serious adverse events (AEs) reported in 44 patients. Most AEs were hematologic events, and the most common of these was myelosuppression (n = 88; 88%). The most common grade 3/4 nonhematologic AE was pulmonary toxicity (n = 7; 12.5%). Thirteen patients were hospitalized for febrile neutropenia for a median of 14 days.

The researchers said patients reported less pain and fewer secondary lesions with guadecitabine than they had with azacitidine.

This trial was sponsored by Groupe Francophone des Myelodysplasies in collaboration with Astex Pharmaceuticals. The researchers reported having no competing interests.

jensmith@mdedge.com

SOURCE: Sébert M et al. Haematologica. 2019 Feb 7. doi: 0.3324/haematol.2018.207118.

New research suggests guadecitabine may be an option for select patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) who have failed treatment with azacitidine.

National Institutes of Health/Wikimedia Commons/Public Domain

In a phase 2 trial, eight of 56 patients with high-risk MDS or low-blast-count AML responded to guadecitabine after azacitidine failure. Patients were significantly more likely to respond if they had few or no somatic mutations.

Marie Sébert, MD, of Hôpital Saint Louis in Paris and her colleagues conducted this trial and reported the results in Haematologica.

The trial (NCT02197676) included 56 patients with the following disease types:

• Refractory anemia with excess blasts (RAEB) type 2 (n = 31; 55%).
• RAEB type 1 (n = 11; 20%).
• Low-blast-count AML (n = 11; 20%).
• Refractory cytopenias with multilineage dysplasia (RCMD; n = 2; 4%).
• Chronic myelomonocytic leukemia (n = 1; 2%).

The patients had a median age of 75 years (range, 70-79) at baseline, and 37 (66%) were men. Thirty-four patients (61%) had very-high-risk disease according to the revised International Prognostic Scoring System. Forty-nine patients (87.5%) had at least one somatic mutation. The most commonly mutated genes were ASXL1, RUNX1, TP53, U2AF1, and DNMT3A.

Most patients (n = 41, 73%) had relapsed after azacitidine, and 15 (27%) had primary resistance to the drug. Patients had received a median of 13 azacitidine cycles (range, 6-23).

The patients received guadecitabine subcutaneously at 60 mg/m² on days 1-5 of a 28-day cycle. They were treated until progression, death, unacceptable toxicity, or no response after six to nine cycles. Patients received a median of three cycles (range, 0-27). One patient died of infection before receiving guadecitabine, but the remaining 55 patients received at least one cycle of treatment. Eighteen patients had a dose reduction.

Eight patients (14.3%) responded to guadecitabine. Two patients achieved a complete response (CR) – one who had RAEB-2 and one with AML. Two patients with RAEB-1 had marrow CRs. Two patients – one with RAEB-2 and one with AML – had marrow CRs with hematologic improvement. A patient with RCMD had hematologic improvement, and a patient with RAEB-2 had a partial response.

The researchers said mutation frequency was the only significant predictor of response. The response rate was significantly higher in patients who did not have somatic mutations (P = .036). The median number of mutations was one (range, zero to three) in responders and two (range, zero to six) in nonresponders (P = .035). None of the patients with TP53 mutations achieved a response.

The median duration of response was 11.5 months. The median overall survival was 17.9 months in responders and 7.1 months in the overall population.

In a multivariate analysis, the following factors were significantly associated with longer survival:
 

• Having low- to high-risk (vs. very-high-risk) disease (P = .03).
• Having experienced primary (vs. secondary) azacitidine failure (P = .01).
• Having a high rate of demethylation in blood during the first treatment cycle (P = .03).

There were 99 serious adverse events (AEs) reported in 44 patients. Most AEs were hematologic events, and the most common of these was myelosuppression (n = 88; 88%). The most common grade 3/4 nonhematologic AE was pulmonary toxicity (n = 7; 12.5%). Thirteen patients were hospitalized for febrile neutropenia for a median of 14 days.

The researchers said patients reported less pain and fewer secondary lesions with guadecitabine than they had with azacitidine.

This trial was sponsored by Groupe Francophone des Myelodysplasies in collaboration with Astex Pharmaceuticals. The researchers reported having no competing interests.

jensmith@mdedge.com

SOURCE: Sébert M et al. Haematologica. 2019 Feb 7. doi: 0.3324/haematol.2018.207118.

A 36-year-old African-American man presented to our clinic for evaluation of a chronic “rash” on his trunk, arms, and legs that had been present for 3 years. Empiric therapy for tinea corporis, nummular eczema, and confluent and reticulated papillomatosis had failed to improve his lesions.

Physical examination revealed a widespread skin eruption consisting of well-demarcated, hyperpigmented, scaly patches and plaques distributed throughout the patient’s trunk and extremities. Initial biopsies of the skin lesions (performed at an outside institution prior to current presentation) were nondiagnostic.

Over the next several months, the patient developed numerous cutaneous nodules and tumors within the background of his persistent patches and plaques (FIGURE). These nodules and tumors intermittently disappeared and recurred, seemingly independent of therapies including psoralen and ultraviolet A phototherapy (PUVA), interferon, and methotrexate.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

 

 

Diagnosis: CD30+ transformed mycosis fungoides

Repeat biopsies ultimately confirmed a diagnosis of mycosis fungoides (MF), a primary cutaneous non-Hodgkin lymphoma of T-cell origin.

Lymphomas occurring in the skin without evidence of disease in other areas of the body at the time of diagnosis are referred to as primary cutaneous lymphomas. They are broadly divided by their cell of origin into cutaneous T-cell and cutaneous B-cell lymphomas. Differentiating primary cutaneous lymphoma from systemic lymphomas with secondary skin involvement is an important distinction, as primary cutaneous lymphomas have different clinical courses and prognoses and require different treatments.¹

One literature review found that 25 unique dermatoses can be mimicked clinically by mycosis fungoides.

MF is the most common type of cutaneous T-cell lymphoma (CTCL), yet it remains an uncommon diagnosis as cutaneous lymphomas comprise only 3.9% of all non-Hodgkin lymphomas.² The CD30+ transformed variant identified in this patient is a rare subtype of MF that is associated with increased morbidity and mortality.³ Other types of CTCL include primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis, and adult T-cell leukemia/lymphoma, all of which can resemble MF clinically and are diagnosed by histopathology.

A nonspecific presentation

Patients with MF typically present with a complaint of chronic, slowly progressive skin lesions of various sizes and morphologies including scaly patches, plaques, and tumors, often in skin distributions that are not directly exposed to the sun (often referred to as a “bathing suit” distribution).⁴ Pruritus typically accompanies these skin lesions, and alopecia and poikiloderma are common findings. Patients with more advanced cases may present with generalized erythroderma. This finding should raise concern for progression to Sézary syndrome, a more aggressive type of CTCL that manifests with leukemic involvement of malignant T-cells matching the T-cell clones found in the skin.²

Alopecia is a common manifestation of MF that can be clinically indistinguishable from alopecia areata.⁵ While isolated alopecia is unlikely to be a consequence of MF, alopecia in the setting of widespread patches and plaques should raise suspicion for a diagnosis of MF.

Continue to: Diagnostic dilemma

 

 

Diagnostic dilemma: Condition mimics benign disorders

This case illustrates the diagnostic dilemma posed by MF due to its propensity to mimic more benign skin disorders, both clinically and histologically.² One literature review of MF cases in which the diagnosis was not suspected clinically but was eventually confirmed histopathologically found that 25 unique dermatoses can be mimicked clinically by MF.⁶ The more common conditions that MF can be mistaken for are discussed below. In light of the diagnostic challenge posed by this multitude of morphologic presentations, referral to Dermatology for histopathologic evaluation is a reasonable next step when empiric treatment fails to improve symptoms of these common skin disorders.

Chronic atopic dermatitis (eczema) is characterized by dry skin and severe pruritis, usually associated with lichenified plaques and a history of atopic disease. The pruritic, scaly plaques typical of MF may be misdiagnosed as eczema; however, a distribution involving the “bathing suit” area is more suggestive of MF. Patients with atopic dermatitis are more likely to display a flexural distribution.²

Tinea corporis typically presents as annular, erythematous, pruritic, scaly patches or plaques that are similar to the scaling lesions of MF. Tinea corporis can be distinguished from MF via potassium hydroxide preparation of skin scrapings from an active lesion, which should demonstrate the segmented hyphae characteristic of this infection. If lesions of this type fail to respond to topical antifungal therapy, a skin biopsy may be warranted for further evaluation.

Nummular eczema, like tinea corporis, presents with round, coin-shaped patches that are highly pruritic and can be difficult to distinguish from the pruritic patches of MF. Unlike MF, however, nummular eczema typically is observed in patients with diffusely dry skin⁷; the lack of this finding should prompt consideration of alternative diagnoses, including MF.

Psoriasis classically presents with symmetrically distributed, well-demarcated plaques with prominent scaling that are usually asymptomatic, but may be associated with pruritis. Psoriatic plaques may be difficult to distinguish clinically from the plaques of MF, but their distribution may offer clues; psoriasis typically follows an extensor surface distribution, whereas MF is more commonly identified in a “bathing suit” or generalized distribution.⁴

Continue to: Tx based on disease extent, impact on quality of life

 

 

Tx based on disease extent, impact on quality of life

Staging of MF is the primary determinant of treatment and involves evaluation of skin, lymph node, viscera, and blood involvement. Early-stage MF has a favorable prognosis and can be effectively managed with skin-directed treatments. These include topical corticosteroids, topical nitrogen mustard agents, topical retinoids, and phototherapy (PUVA).⁸ Total skin electron beam therapy has been proven effective in the treatment of refractory and extensive MF, and local radiation therapy also is an effective treatment for isolated cutaneous tumors. Prolonged complete remissions of early-stage MF have been achieved using skin-directed treatments.⁸

In contrast, advanced MF often is treatment refractory and carries a poor prognosis. Systemic treatments such as interferon therapy, oral retinoids, extracorporeal photopheresis, and chemotherapy are added in patients with advanced disease after skin-directed therapy fails to adequately control tumor burden.

Our patient initially was treated with PUVA as well as 6 million U of interferon alfa-2B 3 times weekly, which he eventually elected to discontinue after 8 months because he wanted to father a child. His disease became more widespread after discontinuing these treatments despite interim therapy with clobetasol ointment .05%. His larger nodules and tumors were intermittently treated with local radiation with good response. Methotrexate 15 mg weekly was initiated following his decline after discontinuing PUVA and interferon treatment. Treatment with methotrexate resulted in an overall decrease in his tumor burden and several months of clinical stability.

Early stage mycosis fungoides has a favorable prognosis and can be effectively managed with skin-directed treatments. Advanced MF often is treatment refractory and has a poor prognosis.

Approximately 6 months after initiating methotrexate, his condition notably worsened. He developed generalized erythroderma, systemic symptoms including fever, chills, and unintentional 9.07-kg weight loss, in addition to new findings of palmoplantar keratoderma and nail dystrophy. In light of this systemic progression and concern for developing Sézary syndrome, extracorporeal photopheresis, bexarotene (an oral retinoid) 75 mg twice daily, and interferon alfa-2B 5 million U 3 times weekly were initiated. His condition continued to decline despite these therapies, culminating in a hospital admission for sepsis.

The patient recovered, and his regimen was changed to PUVA 3 times weekly in addition to treatment with intravenous brentuximab 1.8 mg/kg, a monoclonal antibody that targets CD30 receptors. Unfortunately, his condition continued to decline on this treatment regimen, which was subsequently abandoned in favor of chemotherapy with gemcitabine 1980 mg/250 mL normal saline. The patient was improving clinically with each cycle of gemcitabine and the plan was to transition him to extracorporeal photopheresis and bexarotene for maintenance therapy; however, the patient succumbed to his disease and passed away at the age of 37.

CORRESPONDENCE
Jonathan Banta, MD, PSC 103, Box 3613, APO, AE 09603 jonathan.c.banta.mil@mail.mil

A 36-year-old African-American man presented to our clinic for evaluation of a chronic “rash” on his trunk, arms, and legs that had been present for 3 years. Empiric therapy for tinea corporis, nummular eczema, and confluent and reticulated papillomatosis had failed to improve his lesions.

Physical examination revealed a widespread skin eruption consisting of well-demarcated, hyperpigmented, scaly patches and plaques distributed throughout the patient’s trunk and extremities. Initial biopsies of the skin lesions (performed at an outside institution prior to current presentation) were nondiagnostic.

Over the next several months, the patient developed numerous cutaneous nodules and tumors within the background of his persistent patches and plaques (FIGURE). These nodules and tumors intermittently disappeared and recurred, seemingly independent of therapies including psoralen and ultraviolet A phototherapy (PUVA), interferon, and methotrexate.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

 

 

Diagnosis: CD30+ transformed mycosis fungoides

Repeat biopsies ultimately confirmed a diagnosis of mycosis fungoides (MF), a primary cutaneous non-Hodgkin lymphoma of T-cell origin.

Lymphomas occurring in the skin without evidence of disease in other areas of the body at the time of diagnosis are referred to as primary cutaneous lymphomas. They are broadly divided by their cell of origin into cutaneous T-cell and cutaneous B-cell lymphomas. Differentiating primary cutaneous lymphoma from systemic lymphomas with secondary skin involvement is an important distinction, as primary cutaneous lymphomas have different clinical courses and prognoses and require different treatments.¹

One literature review found that 25 unique dermatoses can be mimicked clinically by mycosis fungoides.

MF is the most common type of cutaneous T-cell lymphoma (CTCL), yet it remains an uncommon diagnosis as cutaneous lymphomas comprise only 3.9% of all non-Hodgkin lymphomas.² The CD30+ transformed variant identified in this patient is a rare subtype of MF that is associated with increased morbidity and mortality.³ Other types of CTCL include primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis, and adult T-cell leukemia/lymphoma, all of which can resemble MF clinically and are diagnosed by histopathology.

A nonspecific presentation

Patients with MF typically present with a complaint of chronic, slowly progressive skin lesions of various sizes and morphologies including scaly patches, plaques, and tumors, often in skin distributions that are not directly exposed to the sun (often referred to as a “bathing suit” distribution).⁴ Pruritus typically accompanies these skin lesions, and alopecia and poikiloderma are common findings. Patients with more advanced cases may present with generalized erythroderma. This finding should raise concern for progression to Sézary syndrome, a more aggressive type of CTCL that manifests with leukemic involvement of malignant T-cells matching the T-cell clones found in the skin.²

Alopecia is a common manifestation of MF that can be clinically indistinguishable from alopecia areata.⁵ While isolated alopecia is unlikely to be a consequence of MF, alopecia in the setting of widespread patches and plaques should raise suspicion for a diagnosis of MF.

Continue to: Diagnostic dilemma

 

 

Diagnostic dilemma: Condition mimics benign disorders

This case illustrates the diagnostic dilemma posed by MF due to its propensity to mimic more benign skin disorders, both clinically and histologically.² One literature review of MF cases in which the diagnosis was not suspected clinically but was eventually confirmed histopathologically found that 25 unique dermatoses can be mimicked clinically by MF.⁶ The more common conditions that MF can be mistaken for are discussed below. In light of the diagnostic challenge posed by this multitude of morphologic presentations, referral to Dermatology for histopathologic evaluation is a reasonable next step when empiric treatment fails to improve symptoms of these common skin disorders.

Chronic atopic dermatitis (eczema) is characterized by dry skin and severe pruritis, usually associated with lichenified plaques and a history of atopic disease. The pruritic, scaly plaques typical of MF may be misdiagnosed as eczema; however, a distribution involving the “bathing suit” area is more suggestive of MF. Patients with atopic dermatitis are more likely to display a flexural distribution.²

Tinea corporis typically presents as annular, erythematous, pruritic, scaly patches or plaques that are similar to the scaling lesions of MF. Tinea corporis can be distinguished from MF via potassium hydroxide preparation of skin scrapings from an active lesion, which should demonstrate the segmented hyphae characteristic of this infection. If lesions of this type fail to respond to topical antifungal therapy, a skin biopsy may be warranted for further evaluation.

Nummular eczema, like tinea corporis, presents with round, coin-shaped patches that are highly pruritic and can be difficult to distinguish from the pruritic patches of MF. Unlike MF, however, nummular eczema typically is observed in patients with diffusely dry skin⁷; the lack of this finding should prompt consideration of alternative diagnoses, including MF.

Psoriasis classically presents with symmetrically distributed, well-demarcated plaques with prominent scaling that are usually asymptomatic, but may be associated with pruritis. Psoriatic plaques may be difficult to distinguish clinically from the plaques of MF, but their distribution may offer clues; psoriasis typically follows an extensor surface distribution, whereas MF is more commonly identified in a “bathing suit” or generalized distribution.⁴

Continue to: Tx based on disease extent, impact on quality of life

 

 

Tx based on disease extent, impact on quality of life

Staging of MF is the primary determinant of treatment and involves evaluation of skin, lymph node, viscera, and blood involvement. Early-stage MF has a favorable prognosis and can be effectively managed with skin-directed treatments. These include topical corticosteroids, topical nitrogen mustard agents, topical retinoids, and phototherapy (PUVA).⁸ Total skin electron beam therapy has been proven effective in the treatment of refractory and extensive MF, and local radiation therapy also is an effective treatment for isolated cutaneous tumors. Prolonged complete remissions of early-stage MF have been achieved using skin-directed treatments.⁸

In contrast, advanced MF often is treatment refractory and carries a poor prognosis. Systemic treatments such as interferon therapy, oral retinoids, extracorporeal photopheresis, and chemotherapy are added in patients with advanced disease after skin-directed therapy fails to adequately control tumor burden.

Our patient initially was treated with PUVA as well as 6 million U of interferon alfa-2B 3 times weekly, which he eventually elected to discontinue after 8 months because he wanted to father a child. His disease became more widespread after discontinuing these treatments despite interim therapy with clobetasol ointment .05%. His larger nodules and tumors were intermittently treated with local radiation with good response. Methotrexate 15 mg weekly was initiated following his decline after discontinuing PUVA and interferon treatment. Treatment with methotrexate resulted in an overall decrease in his tumor burden and several months of clinical stability.

Early stage mycosis fungoides has a favorable prognosis and can be effectively managed with skin-directed treatments. Advanced MF often is treatment refractory and has a poor prognosis.

Approximately 6 months after initiating methotrexate, his condition notably worsened. He developed generalized erythroderma, systemic symptoms including fever, chills, and unintentional 9.07-kg weight loss, in addition to new findings of palmoplantar keratoderma and nail dystrophy. In light of this systemic progression and concern for developing Sézary syndrome, extracorporeal photopheresis, bexarotene (an oral retinoid) 75 mg twice daily, and interferon alfa-2B 5 million U 3 times weekly were initiated. His condition continued to decline despite these therapies, culminating in a hospital admission for sepsis.

The patient recovered, and his regimen was changed to PUVA 3 times weekly in addition to treatment with intravenous brentuximab 1.8 mg/kg, a monoclonal antibody that targets CD30 receptors. Unfortunately, his condition continued to decline on this treatment regimen, which was subsequently abandoned in favor of chemotherapy with gemcitabine 1980 mg/250 mL normal saline. The patient was improving clinically with each cycle of gemcitabine and the plan was to transition him to extracorporeal photopheresis and bexarotene for maintenance therapy; however, the patient succumbed to his disease and passed away at the age of 37.

CORRESPONDENCE
Jonathan Banta, MD, PSC 103, Box 3613, APO, AE 09603 jonathan.c.banta.mil@mail.mil

A 36-year-old African-American man presented to our clinic for evaluation of a chronic “rash” on his trunk, arms, and legs that had been present for 3 years. Empiric therapy for tinea corporis, nummular eczema, and confluent and reticulated papillomatosis had failed to improve his lesions.

Physical examination revealed a widespread skin eruption consisting of well-demarcated, hyperpigmented, scaly patches and plaques distributed throughout the patient’s trunk and extremities. Initial biopsies of the skin lesions (performed at an outside institution prior to current presentation) were nondiagnostic.

Over the next several months, the patient developed numerous cutaneous nodules and tumors within the background of his persistent patches and plaques (FIGURE). These nodules and tumors intermittently disappeared and recurred, seemingly independent of therapies including psoralen and ultraviolet A phototherapy (PUVA), interferon, and methotrexate.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

 

 

Diagnosis: CD30+ transformed mycosis fungoides

Repeat biopsies ultimately confirmed a diagnosis of mycosis fungoides (MF), a primary cutaneous non-Hodgkin lymphoma of T-cell origin.

Lymphomas occurring in the skin without evidence of disease in other areas of the body at the time of diagnosis are referred to as primary cutaneous lymphomas. They are broadly divided by their cell of origin into cutaneous T-cell and cutaneous B-cell lymphomas. Differentiating primary cutaneous lymphoma from systemic lymphomas with secondary skin involvement is an important distinction, as primary cutaneous lymphomas have different clinical courses and prognoses and require different treatments.¹

One literature review found that 25 unique dermatoses can be mimicked clinically by mycosis fungoides.

MF is the most common type of cutaneous T-cell lymphoma (CTCL), yet it remains an uncommon diagnosis as cutaneous lymphomas comprise only 3.9% of all non-Hodgkin lymphomas.² The CD30+ transformed variant identified in this patient is a rare subtype of MF that is associated with increased morbidity and mortality.³ Other types of CTCL include primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis, and adult T-cell leukemia/lymphoma, all of which can resemble MF clinically and are diagnosed by histopathology.

A nonspecific presentation

Patients with MF typically present with a complaint of chronic, slowly progressive skin lesions of various sizes and morphologies including scaly patches, plaques, and tumors, often in skin distributions that are not directly exposed to the sun (often referred to as a “bathing suit” distribution).⁴ Pruritus typically accompanies these skin lesions, and alopecia and poikiloderma are common findings. Patients with more advanced cases may present with generalized erythroderma. This finding should raise concern for progression to Sézary syndrome, a more aggressive type of CTCL that manifests with leukemic involvement of malignant T-cells matching the T-cell clones found in the skin.²

Alopecia is a common manifestation of MF that can be clinically indistinguishable from alopecia areata.⁵ While isolated alopecia is unlikely to be a consequence of MF, alopecia in the setting of widespread patches and plaques should raise suspicion for a diagnosis of MF.

Continue to: Diagnostic dilemma

 

 

Diagnostic dilemma: Condition mimics benign disorders

This case illustrates the diagnostic dilemma posed by MF due to its propensity to mimic more benign skin disorders, both clinically and histologically.² One literature review of MF cases in which the diagnosis was not suspected clinically but was eventually confirmed histopathologically found that 25 unique dermatoses can be mimicked clinically by MF.⁶ The more common conditions that MF can be mistaken for are discussed below. In light of the diagnostic challenge posed by this multitude of morphologic presentations, referral to Dermatology for histopathologic evaluation is a reasonable next step when empiric treatment fails to improve symptoms of these common skin disorders.

Chronic atopic dermatitis (eczema) is characterized by dry skin and severe pruritis, usually associated with lichenified plaques and a history of atopic disease. The pruritic, scaly plaques typical of MF may be misdiagnosed as eczema; however, a distribution involving the “bathing suit” area is more suggestive of MF. Patients with atopic dermatitis are more likely to display a flexural distribution.²

Tinea corporis typically presents as annular, erythematous, pruritic, scaly patches or plaques that are similar to the scaling lesions of MF. Tinea corporis can be distinguished from MF via potassium hydroxide preparation of skin scrapings from an active lesion, which should demonstrate the segmented hyphae characteristic of this infection. If lesions of this type fail to respond to topical antifungal therapy, a skin biopsy may be warranted for further evaluation.

Nummular eczema, like tinea corporis, presents with round, coin-shaped patches that are highly pruritic and can be difficult to distinguish from the pruritic patches of MF. Unlike MF, however, nummular eczema typically is observed in patients with diffusely dry skin⁷; the lack of this finding should prompt consideration of alternative diagnoses, including MF.

Psoriasis classically presents with symmetrically distributed, well-demarcated plaques with prominent scaling that are usually asymptomatic, but may be associated with pruritis. Psoriatic plaques may be difficult to distinguish clinically from the plaques of MF, but their distribution may offer clues; psoriasis typically follows an extensor surface distribution, whereas MF is more commonly identified in a “bathing suit” or generalized distribution.⁴

Continue to: Tx based on disease extent, impact on quality of life

 

 

Tx based on disease extent, impact on quality of life

Staging of MF is the primary determinant of treatment and involves evaluation of skin, lymph node, viscera, and blood involvement. Early-stage MF has a favorable prognosis and can be effectively managed with skin-directed treatments. These include topical corticosteroids, topical nitrogen mustard agents, topical retinoids, and phototherapy (PUVA).⁸ Total skin electron beam therapy has been proven effective in the treatment of refractory and extensive MF, and local radiation therapy also is an effective treatment for isolated cutaneous tumors. Prolonged complete remissions of early-stage MF have been achieved using skin-directed treatments.⁸

In contrast, advanced MF often is treatment refractory and carries a poor prognosis. Systemic treatments such as interferon therapy, oral retinoids, extracorporeal photopheresis, and chemotherapy are added in patients with advanced disease after skin-directed therapy fails to adequately control tumor burden.

Our patient initially was treated with PUVA as well as 6 million U of interferon alfa-2B 3 times weekly, which he eventually elected to discontinue after 8 months because he wanted to father a child. His disease became more widespread after discontinuing these treatments despite interim therapy with clobetasol ointment .05%. His larger nodules and tumors were intermittently treated with local radiation with good response. Methotrexate 15 mg weekly was initiated following his decline after discontinuing PUVA and interferon treatment. Treatment with methotrexate resulted in an overall decrease in his tumor burden and several months of clinical stability.

Early stage mycosis fungoides has a favorable prognosis and can be effectively managed with skin-directed treatments. Advanced MF often is treatment refractory and has a poor prognosis.

Approximately 6 months after initiating methotrexate, his condition notably worsened. He developed generalized erythroderma, systemic symptoms including fever, chills, and unintentional 9.07-kg weight loss, in addition to new findings of palmoplantar keratoderma and nail dystrophy. In light of this systemic progression and concern for developing Sézary syndrome, extracorporeal photopheresis, bexarotene (an oral retinoid) 75 mg twice daily, and interferon alfa-2B 5 million U 3 times weekly were initiated. His condition continued to decline despite these therapies, culminating in a hospital admission for sepsis.

The patient recovered, and his regimen was changed to PUVA 3 times weekly in addition to treatment with intravenous brentuximab 1.8 mg/kg, a monoclonal antibody that targets CD30 receptors. Unfortunately, his condition continued to decline on this treatment regimen, which was subsequently abandoned in favor of chemotherapy with gemcitabine 1980 mg/250 mL normal saline. The patient was improving clinically with each cycle of gemcitabine and the plan was to transition him to extracorporeal photopheresis and bexarotene for maintenance therapy; however, the patient succumbed to his disease and passed away at the age of 37.

CORRESPONDENCE
Jonathan Banta, MD, PSC 103, Box 3613, APO, AE 09603 jonathan.c.banta.mil@mail.mil

HONOLULU – A second-generation hydrogel coil that’s already approved for U.S. marketing proved superior to bare platinum wire for durably embolizing brain aneurysms in a multicenter, randomized trial with 600 patients.

Mitchel L. Zoler/MDedge News

For the study’s primary endpoint of recurrent intracranial aneurysm during follow-up as long as 18-24 months, the 297 patients treated with the hydrogel coil had a recurrence rate of 4%, compared with a 15% rate among patients treated with platinum wire, Bernard R. Bendok, MD, said at the International Stroke Conference sponsored by the American Heart Association. The hydrogel coil materials were also relatively easy to use – much easier than the first-generation hydrogel materials, according to Dr. Bendok – and the adverse event rate using the hydrogel coils was similar to the rate using platinum wire, the standard material for brain aneurysm embolization.

Given the similar safety and ease of use and superior efficacy, clinicians treating brain aneurysms may now increasingly use hydrogel coil. “I think these results will change practice. It’s compelling data,” Dr. Bendok predicted in an interview. “The problem with platinum is it is not conducive to healing.” When an aneurysm is “closed” by insertion of platinum wire, in reality most of the space within the aneurysm remains unfilled by metal. In contrast, animal models suggest that when hydrogel fills an aneurysm it forms a matrix for collagen deposition that further fills the aneurysm space in a wound-healing process, thereby making recurrence less likely, said Dr. Bendok, professor and chair of neurosurgery at the Mayo Clinic in Phoenix.

The HEAT (Hydrogel Endovascular Aneurysm Treatment) trial enrolled patients at 46 centers in the United States and Canada during June 2012–January 2016. Enrolled patients had a ruptured or unruptured brain aneurysm 3-14 mm in diameter, and averaged 57 years old. A blinded core laboratory reviewed brain scans to identify recurrent aneurysms. Of the 297 patients randomized to hydrogel coil treatment, 254 underwent follow-up at 3-12 months and 222 had additional follow-up at 18-24 months, the study’s prespecified time for the primary endpoint. Among 303 patients treated with platinum, 258 had follow-up after 3-12 months and 231 had follow-up at 18-24 months.

Among patients who entered the study with an unruptured aneurysm (nearly three-quarters of enrolled patients), the recurrence rate was 12% with platinum and 3% with hydrogel. Among the patients with a ruptured aneurysm, the recurrence rate was 24% with platinum and 8% with hydrogel. Adverse events occurred in 25% of those treated with platinum and 22% of those treated with hydrogel coil. Mortality during follow-up was 3% in the platinum arm and 2% in the hydrogel coil arm. The two groups also had similar outcomes as measured by the modified Rankin Scale and by quality-of-life measures.

HEAT was sponsored by MicroVention, the company that markets the tested hydrogel coil. Dr. Bendok had no personal disclosures.

mzoler@mdedge.com

SOURCE: Abi-Aad KR et al. ISC 2019, Abstract LB20.

HONOLULU – A second-generation hydrogel coil that’s already approved for U.S. marketing proved superior to bare platinum wire for durably embolizing brain aneurysms in a multicenter, randomized trial with 600 patients.

Mitchel L. Zoler/MDedge News

For the study’s primary endpoint of recurrent intracranial aneurysm during follow-up as long as 18-24 months, the 297 patients treated with the hydrogel coil had a recurrence rate of 4%, compared with a 15% rate among patients treated with platinum wire, Bernard R. Bendok, MD, said at the International Stroke Conference sponsored by the American Heart Association. The hydrogel coil materials were also relatively easy to use – much easier than the first-generation hydrogel materials, according to Dr. Bendok – and the adverse event rate using the hydrogel coils was similar to the rate using platinum wire, the standard material for brain aneurysm embolization.

Given the similar safety and ease of use and superior efficacy, clinicians treating brain aneurysms may now increasingly use hydrogel coil. “I think these results will change practice. It’s compelling data,” Dr. Bendok predicted in an interview. “The problem with platinum is it is not conducive to healing.” When an aneurysm is “closed” by insertion of platinum wire, in reality most of the space within the aneurysm remains unfilled by metal. In contrast, animal models suggest that when hydrogel fills an aneurysm it forms a matrix for collagen deposition that further fills the aneurysm space in a wound-healing process, thereby making recurrence less likely, said Dr. Bendok, professor and chair of neurosurgery at the Mayo Clinic in Phoenix.

The HEAT (Hydrogel Endovascular Aneurysm Treatment) trial enrolled patients at 46 centers in the United States and Canada during June 2012–January 2016. Enrolled patients had a ruptured or unruptured brain aneurysm 3-14 mm in diameter, and averaged 57 years old. A blinded core laboratory reviewed brain scans to identify recurrent aneurysms. Of the 297 patients randomized to hydrogel coil treatment, 254 underwent follow-up at 3-12 months and 222 had additional follow-up at 18-24 months, the study’s prespecified time for the primary endpoint. Among 303 patients treated with platinum, 258 had follow-up after 3-12 months and 231 had follow-up at 18-24 months.

Among patients who entered the study with an unruptured aneurysm (nearly three-quarters of enrolled patients), the recurrence rate was 12% with platinum and 3% with hydrogel. Among the patients with a ruptured aneurysm, the recurrence rate was 24% with platinum and 8% with hydrogel. Adverse events occurred in 25% of those treated with platinum and 22% of those treated with hydrogel coil. Mortality during follow-up was 3% in the platinum arm and 2% in the hydrogel coil arm. The two groups also had similar outcomes as measured by the modified Rankin Scale and by quality-of-life measures.

HEAT was sponsored by MicroVention, the company that markets the tested hydrogel coil. Dr. Bendok had no personal disclosures.

mzoler@mdedge.com

SOURCE: Abi-Aad KR et al. ISC 2019, Abstract LB20.

HONOLULU – A second-generation hydrogel coil that’s already approved for U.S. marketing proved superior to bare platinum wire for durably embolizing brain aneurysms in a multicenter, randomized trial with 600 patients.

Mitchel L. Zoler/MDedge News

For the study’s primary endpoint of recurrent intracranial aneurysm during follow-up as long as 18-24 months, the 297 patients treated with the hydrogel coil had a recurrence rate of 4%, compared with a 15% rate among patients treated with platinum wire, Bernard R. Bendok, MD, said at the International Stroke Conference sponsored by the American Heart Association. The hydrogel coil materials were also relatively easy to use – much easier than the first-generation hydrogel materials, according to Dr. Bendok – and the adverse event rate using the hydrogel coils was similar to the rate using platinum wire, the standard material for brain aneurysm embolization.

Given the similar safety and ease of use and superior efficacy, clinicians treating brain aneurysms may now increasingly use hydrogel coil. “I think these results will change practice. It’s compelling data,” Dr. Bendok predicted in an interview. “The problem with platinum is it is not conducive to healing.” When an aneurysm is “closed” by insertion of platinum wire, in reality most of the space within the aneurysm remains unfilled by metal. In contrast, animal models suggest that when hydrogel fills an aneurysm it forms a matrix for collagen deposition that further fills the aneurysm space in a wound-healing process, thereby making recurrence less likely, said Dr. Bendok, professor and chair of neurosurgery at the Mayo Clinic in Phoenix.

The HEAT (Hydrogel Endovascular Aneurysm Treatment) trial enrolled patients at 46 centers in the United States and Canada during June 2012–January 2016. Enrolled patients had a ruptured or unruptured brain aneurysm 3-14 mm in diameter, and averaged 57 years old. A blinded core laboratory reviewed brain scans to identify recurrent aneurysms. Of the 297 patients randomized to hydrogel coil treatment, 254 underwent follow-up at 3-12 months and 222 had additional follow-up at 18-24 months, the study’s prespecified time for the primary endpoint. Among 303 patients treated with platinum, 258 had follow-up after 3-12 months and 231 had follow-up at 18-24 months.

Among patients who entered the study with an unruptured aneurysm (nearly three-quarters of enrolled patients), the recurrence rate was 12% with platinum and 3% with hydrogel. Among the patients with a ruptured aneurysm, the recurrence rate was 24% with platinum and 8% with hydrogel. Adverse events occurred in 25% of those treated with platinum and 22% of those treated with hydrogel coil. Mortality during follow-up was 3% in the platinum arm and 2% in the hydrogel coil arm. The two groups also had similar outcomes as measured by the modified Rankin Scale and by quality-of-life measures.

HEAT was sponsored by MicroVention, the company that markets the tested hydrogel coil. Dr. Bendok had no personal disclosures.

mzoler@mdedge.com

SOURCE: Abi-Aad KR et al. ISC 2019, Abstract LB20.