ATLANTA – Several studies featured during a press briefing at the annual meeting of the American Association for Cancer Research highlight the types of “transformative strategies” currently being developed and implemented, according to Louis Weiner, MD.

“Had this been the AACR [meeting] 20 years ago ... each one of them would have been a main plenary presentation and would have been the talk of the meeting,” Dr. Weiner, director of the Georgetown Lombardi Cancer Center at Georgetown University, Washington, and press briefing moderator, said of the findings.

While they are well accepted as being high quality presentations of great value, they don’t cause the same amount of stir, he said, adding: “I wouldn’t say we’re jaded, but we’ve come to the point where we almost expect great results at these meetings, and isn’t that wonderful?”

In this video interview he discussed the findings of two of the studies, including the phase 2 UNITY-NHL study and a preclinical Lynch syndrome mouse model used to develop a potential cancer preventive vaccine.

The Lynch syndrome data “suggest the strong possibility that we might be able to immunize people and combine that treatment with standard nonsteroidal anti-inflammatory agents such as naproxen to delay or reduce the impact of Lynch syndrome.”

“This set of findings ... opens the door to investigators in many different areas of cancer research to explore whether or not there are common frameshift mutations that might create novel neoantigens that we can go after with vaccines – be they for therapeutic benefit or for prevention,” he said.

The UNITY-NHL study, which showed that umbralisib is active and well tolerated as single-agent therapy in patients with relapsed or refractory marginal zone lymphoma, suggests “it’s quite possible that [the phosphoinositide 3-kinase delta inhibitor] is going to become a very important element in the treatment of patients with marginal zone lymphomas, and obviously it can be then used in earlier stages of diseases since it’s well tolerated, and it may well have useful activity in other B-cell malignancies,” he said.

Dr. Weiner reported having no relevant disclosures.

ATLANTA – Several studies featured during a press briefing at the annual meeting of the American Association for Cancer Research highlight the types of “transformative strategies” currently being developed and implemented, according to Louis Weiner, MD.

“Had this been the AACR [meeting] 20 years ago ... each one of them would have been a main plenary presentation and would have been the talk of the meeting,” Dr. Weiner, director of the Georgetown Lombardi Cancer Center at Georgetown University, Washington, and press briefing moderator, said of the findings.

While they are well accepted as being high quality presentations of great value, they don’t cause the same amount of stir, he said, adding: “I wouldn’t say we’re jaded, but we’ve come to the point where we almost expect great results at these meetings, and isn’t that wonderful?”

In this video interview he discussed the findings of two of the studies, including the phase 2 UNITY-NHL study and a preclinical Lynch syndrome mouse model used to develop a potential cancer preventive vaccine.

The Lynch syndrome data “suggest the strong possibility that we might be able to immunize people and combine that treatment with standard nonsteroidal anti-inflammatory agents such as naproxen to delay or reduce the impact of Lynch syndrome.”

“This set of findings ... opens the door to investigators in many different areas of cancer research to explore whether or not there are common frameshift mutations that might create novel neoantigens that we can go after with vaccines – be they for therapeutic benefit or for prevention,” he said.

The UNITY-NHL study, which showed that umbralisib is active and well tolerated as single-agent therapy in patients with relapsed or refractory marginal zone lymphoma, suggests “it’s quite possible that [the phosphoinositide 3-kinase delta inhibitor] is going to become a very important element in the treatment of patients with marginal zone lymphomas, and obviously it can be then used in earlier stages of diseases since it’s well tolerated, and it may well have useful activity in other B-cell malignancies,” he said.

Dr. Weiner reported having no relevant disclosures.

ATLANTA – Several studies featured during a press briefing at the annual meeting of the American Association for Cancer Research highlight the types of “transformative strategies” currently being developed and implemented, according to Louis Weiner, MD.

“Had this been the AACR [meeting] 20 years ago ... each one of them would have been a main plenary presentation and would have been the talk of the meeting,” Dr. Weiner, director of the Georgetown Lombardi Cancer Center at Georgetown University, Washington, and press briefing moderator, said of the findings.

While they are well accepted as being high quality presentations of great value, they don’t cause the same amount of stir, he said, adding: “I wouldn’t say we’re jaded, but we’ve come to the point where we almost expect great results at these meetings, and isn’t that wonderful?”

In this video interview he discussed the findings of two of the studies, including the phase 2 UNITY-NHL study and a preclinical Lynch syndrome mouse model used to develop a potential cancer preventive vaccine.

The Lynch syndrome data “suggest the strong possibility that we might be able to immunize people and combine that treatment with standard nonsteroidal anti-inflammatory agents such as naproxen to delay or reduce the impact of Lynch syndrome.”

“This set of findings ... opens the door to investigators in many different areas of cancer research to explore whether or not there are common frameshift mutations that might create novel neoantigens that we can go after with vaccines – be they for therapeutic benefit or for prevention,” he said.

The UNITY-NHL study, which showed that umbralisib is active and well tolerated as single-agent therapy in patients with relapsed or refractory marginal zone lymphoma, suggests “it’s quite possible that [the phosphoinositide 3-kinase delta inhibitor] is going to become a very important element in the treatment of patients with marginal zone lymphomas, and obviously it can be then used in earlier stages of diseases since it’s well tolerated, and it may well have useful activity in other B-cell malignancies,” he said.

Dr. Weiner reported having no relevant disclosures.

Seniors who move into and live in long-term care facilities are at increased risk of suicide, according to reporting by the PBS NewsHour and Kaiser Health News. The report focused on the story of Roland K. Tiedemann, a senior who, in his younger days, was an outdoorsman, traveled around the world, and served as a surrogate dad to his granddaughter. When his health deteriorated, he moved to a long-term care facility with his wife, who later was diagnosed with dementia. At age 89, Mr. Tiedemann, who was facing a third move into a facility that would take Medicaid, “locked his door ... and jumped to his death from his fourth floor window,” the report said. The death of Mr. Tiedemann led Julie A. Rickard, PhD, to start asking questions at his facility and working with other centers to identify the signs of depression. A few years earlier, after a “rash of suicides, mostly among young people,” Dr. Rickard had started developing the Suicide Prevention Coalition of North Central Washington. After looking into policies at long-term care facilities, Dr. Rickard began recommending changes that she hoped would prove protective. For example, in some cases, residents are “paired with people who are not adjusting well to those who are.” It is also important for families to ask whether suicide prevention and mental health protocols are in place at long-term care facilities. Ultimately, Dr. Rickard and Jane Davis – Mr. Tiedemann’s daughter – agree that stigma needs to be reduced so that residents feel free to talk their depression and anxiety. PBS NewsHour.

Dundanim/shutterstock.com

Police officers trained in helping people with mental health problems can get positive results, a newspaper report shows. That’s what happened when Logan Elliott called Clive, Iowa, police to report that his fiancé had threatened suicide – and had had a prior attempt, according to the Des Moines Register. Mr. Elliott’s fiancé, Codii Lewis, was in a “depressive state,” was suffering from the loss of his dog, and was troubled by uncertainty regarding the cost of a procedure undertaken to confirm his gender as a transgender man; as a result, Mr. Lewis climbed onto a ledge. He streamed video of his encounter with the police on Facebook Live, and eventually, after kicking one of the officers, he was subdued and taken into custody. The training that Clive officers receive “calls for less aggressive behavior by police,” the article said. “It emphasizes de-escalation, especially when the subject may be suicidal. It doesn’t expect officers to be therapists or handle all mental health situations, but it does ask that they handle mental health situations differently” from the way they might handle other calls. People with mental illness that is untreated are 16 times more likely to be killed by law enforcement than are people without mental illness. Des Moines Register.

An exhibit now running at the Dartmouth-Hitchcock Medical Center in Lebanon, N.H., is intended to put a human face on mental illness. The 99 Faces Project: Portraits Without Labels by Boston-area artist Lynda Michaud Cutrell presents photos of people with serious mental illnesses and those who love them, the New Hampshire Union Leader reported. Portraits were taken with the help of three photographers nationwide. The long list was trimmed to 99 that mirror the ethnic makeup of the U.S. population. The roster of individuals includes 33 with schizophrenia and 33 with bipolar disorder. The remaining 33 are “chronically normal” according to Ms. Cutrell. The viewer can’t tell the difference between the mentally affected individuals and those who are not; they look like people one encounters every day. And that’s the point. Marianne Barthel, director of the Dartmouth-Hitchcock Arts Program, hopes the exhibit leads to conversations that help “normalize mental health in our society, to recognize that the people you’re looking at in these images could be you or your family member,” the article said. Ms. Barthel also hopes that the exhibit, which runs until September, will help reduce the stigma around mental illness by showing that “there are people who are living successful lives with these illnesses.” One of the 99 faces is that of actress Glenn Close, who cofounded the organization Bring Change To Mind in 2010 after her sister was diagnosed with bipolar disorder and her nephew with schizoaffective disorder. New Hampshire Union Leader.

Deliberation about the use of the death penalty for a prisoner in Kansas has implications for those with mental illness who commit crimes. As the Topeka Capital-Journal reported, James Kahler was convicted of murdering his estranged wife, her grandmother, and his two teenage daughters in 2009. Two years later, he was sentenced to death, and several years later, the Kansas Supreme Court upheld that conviction. His guilt is not in question. What is at issue is his impairment. His lawyers had earlier argued that severe depression had made his grip on reality tenuous and that he could not be executed. Now comes the news that the U.S. Supreme Court will rule whether the decision by the state of Kansas to abolish insanity as a defense was constitutional under the 8th and 14th amendments. The high court’s ruling will have profound implications for people with mental illness. In addition to those in Kansas, under state laws in Alaska, Idaho, Montana, and Utah, “a traditional insanity defense in which a person must understand the difference between right and wrong before being found guilty of a crime isn’t allowed,” the report said. An accused can cite “mental disease or defect” as a partial defense. However, in such cases, it must be proven that the person had no intention of committing a crime. In their petition to the Supreme Court, his attorneys argued that he knew he was shooting people, but that he was so disturbed at the time that he could not stop himself. “A favorable decision would make it clear that the Constitution requires that a defendant be able to understand the difference between right and wrong before being found guilty, and, in cases like Mr. Kahler’s, put to death,” his defense attorney, Meryle Carver-Allmond, told the Capital-Journal. “We’re hopeful that, in taking Mr. Kahler’s case, the United States Supreme Court has indicated a desire to find that the Constitution requires better of us in our treatment of mentally ill defendants.” The Topeka Capital-Journal.

Seniors who move into and live in long-term care facilities are at increased risk of suicide, according to reporting by the PBS NewsHour and Kaiser Health News. The report focused on the story of Roland K. Tiedemann, a senior who, in his younger days, was an outdoorsman, traveled around the world, and served as a surrogate dad to his granddaughter. When his health deteriorated, he moved to a long-term care facility with his wife, who later was diagnosed with dementia. At age 89, Mr. Tiedemann, who was facing a third move into a facility that would take Medicaid, “locked his door ... and jumped to his death from his fourth floor window,” the report said. The death of Mr. Tiedemann led Julie A. Rickard, PhD, to start asking questions at his facility and working with other centers to identify the signs of depression. A few years earlier, after a “rash of suicides, mostly among young people,” Dr. Rickard had started developing the Suicide Prevention Coalition of North Central Washington. After looking into policies at long-term care facilities, Dr. Rickard began recommending changes that she hoped would prove protective. For example, in some cases, residents are “paired with people who are not adjusting well to those who are.” It is also important for families to ask whether suicide prevention and mental health protocols are in place at long-term care facilities. Ultimately, Dr. Rickard and Jane Davis – Mr. Tiedemann’s daughter – agree that stigma needs to be reduced so that residents feel free to talk their depression and anxiety. PBS NewsHour.

Dundanim/shutterstock.com

Police officers trained in helping people with mental health problems can get positive results, a newspaper report shows. That’s what happened when Logan Elliott called Clive, Iowa, police to report that his fiancé had threatened suicide – and had had a prior attempt, according to the Des Moines Register. Mr. Elliott’s fiancé, Codii Lewis, was in a “depressive state,” was suffering from the loss of his dog, and was troubled by uncertainty regarding the cost of a procedure undertaken to confirm his gender as a transgender man; as a result, Mr. Lewis climbed onto a ledge. He streamed video of his encounter with the police on Facebook Live, and eventually, after kicking one of the officers, he was subdued and taken into custody. The training that Clive officers receive “calls for less aggressive behavior by police,” the article said. “It emphasizes de-escalation, especially when the subject may be suicidal. It doesn’t expect officers to be therapists or handle all mental health situations, but it does ask that they handle mental health situations differently” from the way they might handle other calls. People with mental illness that is untreated are 16 times more likely to be killed by law enforcement than are people without mental illness. Des Moines Register.

An exhibit now running at the Dartmouth-Hitchcock Medical Center in Lebanon, N.H., is intended to put a human face on mental illness. The 99 Faces Project: Portraits Without Labels by Boston-area artist Lynda Michaud Cutrell presents photos of people with serious mental illnesses and those who love them, the New Hampshire Union Leader reported. Portraits were taken with the help of three photographers nationwide. The long list was trimmed to 99 that mirror the ethnic makeup of the U.S. population. The roster of individuals includes 33 with schizophrenia and 33 with bipolar disorder. The remaining 33 are “chronically normal” according to Ms. Cutrell. The viewer can’t tell the difference between the mentally affected individuals and those who are not; they look like people one encounters every day. And that’s the point. Marianne Barthel, director of the Dartmouth-Hitchcock Arts Program, hopes the exhibit leads to conversations that help “normalize mental health in our society, to recognize that the people you’re looking at in these images could be you or your family member,” the article said. Ms. Barthel also hopes that the exhibit, which runs until September, will help reduce the stigma around mental illness by showing that “there are people who are living successful lives with these illnesses.” One of the 99 faces is that of actress Glenn Close, who cofounded the organization Bring Change To Mind in 2010 after her sister was diagnosed with bipolar disorder and her nephew with schizoaffective disorder. New Hampshire Union Leader.

Deliberation about the use of the death penalty for a prisoner in Kansas has implications for those with mental illness who commit crimes. As the Topeka Capital-Journal reported, James Kahler was convicted of murdering his estranged wife, her grandmother, and his two teenage daughters in 2009. Two years later, he was sentenced to death, and several years later, the Kansas Supreme Court upheld that conviction. His guilt is not in question. What is at issue is his impairment. His lawyers had earlier argued that severe depression had made his grip on reality tenuous and that he could not be executed. Now comes the news that the U.S. Supreme Court will rule whether the decision by the state of Kansas to abolish insanity as a defense was constitutional under the 8th and 14th amendments. The high court’s ruling will have profound implications for people with mental illness. In addition to those in Kansas, under state laws in Alaska, Idaho, Montana, and Utah, “a traditional insanity defense in which a person must understand the difference between right and wrong before being found guilty of a crime isn’t allowed,” the report said. An accused can cite “mental disease or defect” as a partial defense. However, in such cases, it must be proven that the person had no intention of committing a crime. In their petition to the Supreme Court, his attorneys argued that he knew he was shooting people, but that he was so disturbed at the time that he could not stop himself. “A favorable decision would make it clear that the Constitution requires that a defendant be able to understand the difference between right and wrong before being found guilty, and, in cases like Mr. Kahler’s, put to death,” his defense attorney, Meryle Carver-Allmond, told the Capital-Journal. “We’re hopeful that, in taking Mr. Kahler’s case, the United States Supreme Court has indicated a desire to find that the Constitution requires better of us in our treatment of mentally ill defendants.” The Topeka Capital-Journal.

Seniors who move into and live in long-term care facilities are at increased risk of suicide, according to reporting by the PBS NewsHour and Kaiser Health News. The report focused on the story of Roland K. Tiedemann, a senior who, in his younger days, was an outdoorsman, traveled around the world, and served as a surrogate dad to his granddaughter. When his health deteriorated, he moved to a long-term care facility with his wife, who later was diagnosed with dementia. At age 89, Mr. Tiedemann, who was facing a third move into a facility that would take Medicaid, “locked his door ... and jumped to his death from his fourth floor window,” the report said. The death of Mr. Tiedemann led Julie A. Rickard, PhD, to start asking questions at his facility and working with other centers to identify the signs of depression. A few years earlier, after a “rash of suicides, mostly among young people,” Dr. Rickard had started developing the Suicide Prevention Coalition of North Central Washington. After looking into policies at long-term care facilities, Dr. Rickard began recommending changes that she hoped would prove protective. For example, in some cases, residents are “paired with people who are not adjusting well to those who are.” It is also important for families to ask whether suicide prevention and mental health protocols are in place at long-term care facilities. Ultimately, Dr. Rickard and Jane Davis – Mr. Tiedemann’s daughter – agree that stigma needs to be reduced so that residents feel free to talk their depression and anxiety. PBS NewsHour.

Dundanim/shutterstock.com

Police officers trained in helping people with mental health problems can get positive results, a newspaper report shows. That’s what happened when Logan Elliott called Clive, Iowa, police to report that his fiancé had threatened suicide – and had had a prior attempt, according to the Des Moines Register. Mr. Elliott’s fiancé, Codii Lewis, was in a “depressive state,” was suffering from the loss of his dog, and was troubled by uncertainty regarding the cost of a procedure undertaken to confirm his gender as a transgender man; as a result, Mr. Lewis climbed onto a ledge. He streamed video of his encounter with the police on Facebook Live, and eventually, after kicking one of the officers, he was subdued and taken into custody. The training that Clive officers receive “calls for less aggressive behavior by police,” the article said. “It emphasizes de-escalation, especially when the subject may be suicidal. It doesn’t expect officers to be therapists or handle all mental health situations, but it does ask that they handle mental health situations differently” from the way they might handle other calls. People with mental illness that is untreated are 16 times more likely to be killed by law enforcement than are people without mental illness. Des Moines Register.

An exhibit now running at the Dartmouth-Hitchcock Medical Center in Lebanon, N.H., is intended to put a human face on mental illness. The 99 Faces Project: Portraits Without Labels by Boston-area artist Lynda Michaud Cutrell presents photos of people with serious mental illnesses and those who love them, the New Hampshire Union Leader reported. Portraits were taken with the help of three photographers nationwide. The long list was trimmed to 99 that mirror the ethnic makeup of the U.S. population. The roster of individuals includes 33 with schizophrenia and 33 with bipolar disorder. The remaining 33 are “chronically normal” according to Ms. Cutrell. The viewer can’t tell the difference between the mentally affected individuals and those who are not; they look like people one encounters every day. And that’s the point. Marianne Barthel, director of the Dartmouth-Hitchcock Arts Program, hopes the exhibit leads to conversations that help “normalize mental health in our society, to recognize that the people you’re looking at in these images could be you or your family member,” the article said. Ms. Barthel also hopes that the exhibit, which runs until September, will help reduce the stigma around mental illness by showing that “there are people who are living successful lives with these illnesses.” One of the 99 faces is that of actress Glenn Close, who cofounded the organization Bring Change To Mind in 2010 after her sister was diagnosed with bipolar disorder and her nephew with schizoaffective disorder. New Hampshire Union Leader.

Deliberation about the use of the death penalty for a prisoner in Kansas has implications for those with mental illness who commit crimes. As the Topeka Capital-Journal reported, James Kahler was convicted of murdering his estranged wife, her grandmother, and his two teenage daughters in 2009. Two years later, he was sentenced to death, and several years later, the Kansas Supreme Court upheld that conviction. His guilt is not in question. What is at issue is his impairment. His lawyers had earlier argued that severe depression had made his grip on reality tenuous and that he could not be executed. Now comes the news that the U.S. Supreme Court will rule whether the decision by the state of Kansas to abolish insanity as a defense was constitutional under the 8th and 14th amendments. The high court’s ruling will have profound implications for people with mental illness. In addition to those in Kansas, under state laws in Alaska, Idaho, Montana, and Utah, “a traditional insanity defense in which a person must understand the difference between right and wrong before being found guilty of a crime isn’t allowed,” the report said. An accused can cite “mental disease or defect” as a partial defense. However, in such cases, it must be proven that the person had no intention of committing a crime. In their petition to the Supreme Court, his attorneys argued that he knew he was shooting people, but that he was so disturbed at the time that he could not stop himself. “A favorable decision would make it clear that the Constitution requires that a defendant be able to understand the difference between right and wrong before being found guilty, and, in cases like Mr. Kahler’s, put to death,” his defense attorney, Meryle Carver-Allmond, told the Capital-Journal. “We’re hopeful that, in taking Mr. Kahler’s case, the United States Supreme Court has indicated a desire to find that the Constitution requires better of us in our treatment of mentally ill defendants.” The Topeka Capital-Journal.

Stress disorders triggered by life events or trauma have a marked deleterious impact on the cardiovascular system, especially in the short term, suggests a Swedish population-based cohort study of more than 1.6 million people.

Previous studies have had limited power to detect associations and have seldom explored conditions other than PTSD, noted the investigators, led by Huan Song, PhD. In addition, little is known about how genetic predisposition to cardiovascular disease may influence the association.

Results of the new study, reported online in the BMJ, showed that with a median follow-up of about 6.5 years, relative to unaffected siblings, patients who had PTSD, acute stress reaction, adjustment disorder, or another stress reaction had a 64% higher risk of developing a cardiovascular disease during the first year post diagnosis, and a 29% higher risk thereafter.

In the first year, risk was most elevated for heart failure – nearly seven times higher for the patients than for their siblings. In addition, overall risk was increased to a significantly greater extent for cardiovascular diseases with early onset, starting before age 50 years, than for those with later onset, according to Dr. Song of the Center of Public Health Sciences at the University of Iceland, Reykjavík, and the Karolinska Institutet in Stockholm. Findings were essentially the same when patients were instead compared with age- and sex-matched individuals from the general population.

“Stress-related disorders are robustly associated with multiple types of cardiovascular disease, independently of familial background, history of somatic/psychiatric diseases, and psychiatric comorbidity,” Dr. Song and her coinvestigators wrote. “These findings call for enhanced clinical awareness and, if verified, monitoring or early intervention among patients with recently diagnosed stress related disorders.”

Study details

In their population-based cohort study of the Swedish National Patient Register, the investigators identified 136,637 patients with new-onset, stress-related disorders diagnosed between 1987 and 2013. They compared these patients with 171,314 unaffected full siblings and with 1,366,370 unaffected matched people from the general population. Median follow-up was 6.2 years, 6.9 years, and 6.5 years, respectively.

Results showed that the crude incidence rate of any cardiovascular disease was 10.5 per 1,000 person years among the patients with stress-related disorders, 8.4 per 1,000 person years among their unaffected siblings, and 6.9 per 1,000 person years among the matched unaffected individuals from the general population.

Compared with unaffected siblings, patients with stress-related disorders had a 60% elevated risk for developing any cardiovascular disease during the first year after diagnosis. Risk in this window was most elevated for heart failure (hazard ratio, 6.95); cerebrovascular disease other than ischemic and hemorrhagic stroke and arachnoidal bleeding (HR, 5.64), conduction disorders (HR, 5.00), and cardiac arrest (HR, 3.37).

Risk of any cardiovascular disease associated with stress-related disorders was still elevated but to a lesser extent after the first year post diagnosis (HR, 1.29). During this period, risk was most elevated for arterial thrombosis/embolus (HR, 2.02), hemorrhagic stroke (HR, 1.56), and fatal cerebrovascular events (HR, 1.56).

In analyses looking at age of onset of the cardiovascular disease, stress-related disorders showed stronger association with early-onset disease (occurring before age 50 years) than with later-onset disease (HR, 1.40 vs. 1.24; P = .002).

Fatal cardiovascular disease was the only category for which the associations were modified by presence of psychiatric comorbidity. Here, presence of such comorbidity amplified the risk conferred by the stress-related disorder.

Findings were much the same when patients were compared with matched individuals from the general population. Risk for any cardiovascular disease was again elevated substantially in the first year post diagnosis by 71%, and to 36% thereafter.

The authors reported that they had no relevant conflicts of interest. The study was supported by the Icelandic Research Fund, an ERC Consolidator Grant, the Karolinska Institutet, and the Swedish Research Council.

SOURCE: Song H et al. BMJ. 2019 Apr 10. doi: 10.1136/bmj.l1255.

Stress disorders triggered by life events or trauma have a marked deleterious impact on the cardiovascular system, especially in the short term, suggests a Swedish population-based cohort study of more than 1.6 million people.

Previous studies have had limited power to detect associations and have seldom explored conditions other than PTSD, noted the investigators, led by Huan Song, PhD. In addition, little is known about how genetic predisposition to cardiovascular disease may influence the association.

Results of the new study, reported online in the BMJ, showed that with a median follow-up of about 6.5 years, relative to unaffected siblings, patients who had PTSD, acute stress reaction, adjustment disorder, or another stress reaction had a 64% higher risk of developing a cardiovascular disease during the first year post diagnosis, and a 29% higher risk thereafter.

In the first year, risk was most elevated for heart failure – nearly seven times higher for the patients than for their siblings. In addition, overall risk was increased to a significantly greater extent for cardiovascular diseases with early onset, starting before age 50 years, than for those with later onset, according to Dr. Song of the Center of Public Health Sciences at the University of Iceland, Reykjavík, and the Karolinska Institutet in Stockholm. Findings were essentially the same when patients were instead compared with age- and sex-matched individuals from the general population.

“Stress-related disorders are robustly associated with multiple types of cardiovascular disease, independently of familial background, history of somatic/psychiatric diseases, and psychiatric comorbidity,” Dr. Song and her coinvestigators wrote. “These findings call for enhanced clinical awareness and, if verified, monitoring or early intervention among patients with recently diagnosed stress related disorders.”

Study details

In their population-based cohort study of the Swedish National Patient Register, the investigators identified 136,637 patients with new-onset, stress-related disorders diagnosed between 1987 and 2013. They compared these patients with 171,314 unaffected full siblings and with 1,366,370 unaffected matched people from the general population. Median follow-up was 6.2 years, 6.9 years, and 6.5 years, respectively.

Results showed that the crude incidence rate of any cardiovascular disease was 10.5 per 1,000 person years among the patients with stress-related disorders, 8.4 per 1,000 person years among their unaffected siblings, and 6.9 per 1,000 person years among the matched unaffected individuals from the general population.

Compared with unaffected siblings, patients with stress-related disorders had a 60% elevated risk for developing any cardiovascular disease during the first year after diagnosis. Risk in this window was most elevated for heart failure (hazard ratio, 6.95); cerebrovascular disease other than ischemic and hemorrhagic stroke and arachnoidal bleeding (HR, 5.64), conduction disorders (HR, 5.00), and cardiac arrest (HR, 3.37).

Risk of any cardiovascular disease associated with stress-related disorders was still elevated but to a lesser extent after the first year post diagnosis (HR, 1.29). During this period, risk was most elevated for arterial thrombosis/embolus (HR, 2.02), hemorrhagic stroke (HR, 1.56), and fatal cerebrovascular events (HR, 1.56).

In analyses looking at age of onset of the cardiovascular disease, stress-related disorders showed stronger association with early-onset disease (occurring before age 50 years) than with later-onset disease (HR, 1.40 vs. 1.24; P = .002).

Fatal cardiovascular disease was the only category for which the associations were modified by presence of psychiatric comorbidity. Here, presence of such comorbidity amplified the risk conferred by the stress-related disorder.

Findings were much the same when patients were compared with matched individuals from the general population. Risk for any cardiovascular disease was again elevated substantially in the first year post diagnosis by 71%, and to 36% thereafter.

The authors reported that they had no relevant conflicts of interest. The study was supported by the Icelandic Research Fund, an ERC Consolidator Grant, the Karolinska Institutet, and the Swedish Research Council.

SOURCE: Song H et al. BMJ. 2019 Apr 10. doi: 10.1136/bmj.l1255.

Stress disorders triggered by life events or trauma have a marked deleterious impact on the cardiovascular system, especially in the short term, suggests a Swedish population-based cohort study of more than 1.6 million people.

Previous studies have had limited power to detect associations and have seldom explored conditions other than PTSD, noted the investigators, led by Huan Song, PhD. In addition, little is known about how genetic predisposition to cardiovascular disease may influence the association.

Results of the new study, reported online in the BMJ, showed that with a median follow-up of about 6.5 years, relative to unaffected siblings, patients who had PTSD, acute stress reaction, adjustment disorder, or another stress reaction had a 64% higher risk of developing a cardiovascular disease during the first year post diagnosis, and a 29% higher risk thereafter.

In the first year, risk was most elevated for heart failure – nearly seven times higher for the patients than for their siblings. In addition, overall risk was increased to a significantly greater extent for cardiovascular diseases with early onset, starting before age 50 years, than for those with later onset, according to Dr. Song of the Center of Public Health Sciences at the University of Iceland, Reykjavík, and the Karolinska Institutet in Stockholm. Findings were essentially the same when patients were instead compared with age- and sex-matched individuals from the general population.

“Stress-related disorders are robustly associated with multiple types of cardiovascular disease, independently of familial background, history of somatic/psychiatric diseases, and psychiatric comorbidity,” Dr. Song and her coinvestigators wrote. “These findings call for enhanced clinical awareness and, if verified, monitoring or early intervention among patients with recently diagnosed stress related disorders.”

Study details

In their population-based cohort study of the Swedish National Patient Register, the investigators identified 136,637 patients with new-onset, stress-related disorders diagnosed between 1987 and 2013. They compared these patients with 171,314 unaffected full siblings and with 1,366,370 unaffected matched people from the general population. Median follow-up was 6.2 years, 6.9 years, and 6.5 years, respectively.

Results showed that the crude incidence rate of any cardiovascular disease was 10.5 per 1,000 person years among the patients with stress-related disorders, 8.4 per 1,000 person years among their unaffected siblings, and 6.9 per 1,000 person years among the matched unaffected individuals from the general population.

Compared with unaffected siblings, patients with stress-related disorders had a 60% elevated risk for developing any cardiovascular disease during the first year after diagnosis. Risk in this window was most elevated for heart failure (hazard ratio, 6.95); cerebrovascular disease other than ischemic and hemorrhagic stroke and arachnoidal bleeding (HR, 5.64), conduction disorders (HR, 5.00), and cardiac arrest (HR, 3.37).

Risk of any cardiovascular disease associated with stress-related disorders was still elevated but to a lesser extent after the first year post diagnosis (HR, 1.29). During this period, risk was most elevated for arterial thrombosis/embolus (HR, 2.02), hemorrhagic stroke (HR, 1.56), and fatal cerebrovascular events (HR, 1.56).

In analyses looking at age of onset of the cardiovascular disease, stress-related disorders showed stronger association with early-onset disease (occurring before age 50 years) than with later-onset disease (HR, 1.40 vs. 1.24; P = .002).

Fatal cardiovascular disease was the only category for which the associations were modified by presence of psychiatric comorbidity. Here, presence of such comorbidity amplified the risk conferred by the stress-related disorder.

Findings were much the same when patients were compared with matched individuals from the general population. Risk for any cardiovascular disease was again elevated substantially in the first year post diagnosis by 71%, and to 36% thereafter.

The authors reported that they had no relevant conflicts of interest. The study was supported by the Icelandic Research Fund, an ERC Consolidator Grant, the Karolinska Institutet, and the Swedish Research Council.

SOURCE: Song H et al. BMJ. 2019 Apr 10. doi: 10.1136/bmj.l1255.

Sézary syndrome (SS) is an advanced leukemic form of cutaneous T-cell lymphoma (CTCL) that is characterized by generalized erythroderma and T-cell leukemia. Skin changes can include erythroderma, keratosis pilaris–like lesions, keratoderma, ectropion, alopecia, and nail changes.¹ Nail changes in SS patients frequently are overlooked and underreported; they vary greatly from patient to patient, and their incidence has not been widely evaluated in the literature.

In this retrospective study, we reviewed medical records from a previously collected CTCL clinic database at the University of Texas MD Anderson Cancer Center (Houston, Texas) and found nail abnormalities in 36 of 83 (43.4%) patients with a diagnosis of SS. Findings for 2 select cases are described in more detail; they were compared to prior case reports from the literature to establish a comprehensive list of nail irregularities that have been associated with SS.

Methods

We examined records from a previously collected CTCL clinic database at the University of Texas MD Anderson Cancer Center. This database was part of an institutional review board–approved protocol to prospectively collect data from patients with CTCL. Our search yielded 83 patients with SS who were seen between 2007 and 2014.

Results

Of the 83 cases reviewed from the CTCL database, 36 (43.4%) SS patients reported at least 1 nail abnormality on the fingernails or toenails. Patients ranged in age from 59 to 85 years and included 27 (75%) men and 9 (25%) women. Nail irregularities noted on physical examination are summarized in Table 1. More than half of the patients presented with nail thickening (58.3% [21/36]), dystrophy (55.6% [20/36]), or yellowing (55.6% [20/36]) of 1 or more nails. Other findings included 15 (41.7%) patients with subungual hyperkeratosis, 3 (8.3%) with Beau lines, and 1 (2.8%) with multiple oil spots consistent with salmon patches. Five (13.9%) patients had only 1 reported nail irregularity, and 1 (2.8%) patient had 6 irregularities. The average number of nail abnormalities per patient was 2.88 (range, 1–6). We selected 2 patients with extensive nail findings who represent the spectrum of nail findings in patients with SS.

Patient 1
A 71-year-old white man presented with a papular rash of 30 years’ duration. The eruption first occurred on the soles of the feet but progressed to generalized erythroderma. He was found to be colonized with methicillin-resistant Staphylococcus aureus. Over the next 9 months, the patient was diagnosed with SS at an outside institution and was treated with cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone, gemcitabine, etoposide, methylprednisolone, cytarabine, cisplatin, topical steroids, and intravenous methotrexate with no apparent improvement. At presentation to our institution, physical examination revealed pruritus; alopecia; generalized lymphadenopathy; erythroderma; and irregular nail findings, including yellowing, thickened fingernails and toenails with subungual debris, and splinter hemorrhage (Figure 1). A thick plaque with perioral distribution as well as erosions on the face and feet were noted. The total body surface area (BSA) affected was 100% (patches, 91%; plaques, 9%).

At diagnosis at our institution, the patient’s white blood cell (WBC) count was 17,800/µL (reference range, 4000–11,000/µL), with 11% Sézary cells noted. Biopsy of a lymph node from the inguinal area indicated T-cell lymphoma with clonal T-cell receptor (TCR) β gene rearrangement. Biopsy of lesional skin in the right groin area showed an atypical T-cell lymphocytic infiltrate with a CD4:CD8 ratio of 2.9:1 and partial loss of CD7 expression, consistent with mycosis fungoides (MF)/SS stage IVA. At presentation to our institution, the WBC count was 12,700/µL with a neutrophil count of 47% (reference range, 42%–66%), lymphocyte count of 36% (reference range, 24%–44%), monocyte count of 4% (reference range, 2%–7%), platelet count of 427,000/µL (reference range, 150,000–350,000/µL), hemoglobin of 9.9 g/dL (reference range, 14.0–17.5 g/dL), and lactate dehydrogenase of 733 U/L (reference range, 135–214 U/L). Lymphocytes were positive for CD2, CD3, CD4, CD5, CD25, CD52, TCRα, TCRβ, and TCR VB17; partial for CD26; and negative for CD7, CD8, and CD57. At follow-up 1 month later, the CD4⁺CD26⁻ T-cell population was 56%, which was consistent with SS T-cell lymphoma.

Skin scrapings from the generalized keratoderma on the patient’s feet were positive for fungal hyphae under potassium hydroxide examination. Nail clippings showed compact keratin with periodic acid–Schiff–positive small yeast forms admixed with bacterial organisms, consistent with onychomycosis. At our institution, the patient received extracorporeal photopheresis, whirlpool therapy (a type of hydrotherapy), steroid wet wraps, and intravenous vancomycin for methicillin-resistant S aureus. He also received bexarotene, levothyroxine sodium, and fenofibrate. After antibiotics and 2 sessions of photopheresis, the total BSA improved from 100% to 33%. The feet and nails were treated with ciclopirox gel and terbinafine, but neither the keratoderma nor the nails improved.

Patient 2
An 84-year-old white man with B-cell chronic lymphocytic leukemia also was diagnosed with SS at an outside institution. One year later, he presented to our institution with mild pruritus and swelling of the lower left leg, which was diagnosed as deep vein thrombosis. There was bilateral scaling of the palms, with fissures present on the left palm. The fingernails showed dystrophy with Beau lines, and the toenails were dystrophic with onycholysis on the bilateral great toes (Figure 2). Patches were noted on most of the body, including the feet, with plaques limited to the hands; the total BSA affected was 80%. Flow cytometry showed an elevated Sézary cell count (CD4⁺CD26⁻) of 4700 cells/µL. Complete blood cell count with differential included a hemoglobin level of 11.4 g/dL, hematocrit level of 35.3% (reference range, 37%–47%), a platelet count of 217,000/µL, and a WBC count of 17,700/µL, of which 29% were neutrophils, 63% were lymphocytes, 6% were monocytes, and 2% were eosinophils. The lactate dehydrogenase level was elevated at 829 U/L. The patient had not been treated for chronic lymphocytic leukemia in the last 11 months due to adverse reactions to rituximab after 2 cycles of fludarabine, cyclophosphamide, and rituximab chemotherapy. First-line therapy for the patient was photopheresis for SS.

Comment

Nail changes are found in many cases of advanced-stage SS but rarely have been reported in the literature. A literature review of PubMed articles indexed for MEDLINE was conducted using the search terms Sézary, nail, onychodystrophy, cutaneous T-cell lymphoma, and CTCL. All results were reviewed for original reported cases of SS with at least 1 reported nail finding. A total of 7 reports^2-8 met these requirements with a total of 43 SS patients with reported nail findings, which are summarized in Tables 2 and 3.

Our findings are generally consistent with those previously described in the literature. Nail thickening, yellowing, subungual hyperkeratosis, dystrophy, and onycholysis are consistently some of the most common nail findings in patients with SS. In 2012, Martin and Duvic⁹ found that 52.9% (45/85) of SS patients with keratoderma on physical examination were positive for dermatophyte hyphae when skin scrapings were done under potassium hydroxide examination, a considerably greater incidence than in the general population (10%–20%). The nail changes seen in our SS patients were identical to those found in dermatophyte infections, including discoloration, subungual debris, nail thickening, onycholysis, and dystrophy.¹⁰ In patient 1, nail clippings were positive for onychomycosis, a common nail condition that is especially prevalent in older or immunocompromised patients.^9,10

Interestingly, findings not observed in the literature included salmon patches and Beau lines. Beau lines are horizontal depressions in the nail plate and often are indicative of temporary interruption of nail growth, such as due to an underlying disease process, severe illness, and/or chemotherapy.^11,12 In our review, patient 2 had clinical findings of Beau lines. Because the average time for fingernail regrowth is 3 to 6 months,¹³ it is reasonable to assume that physical findings associated with fludarabine, cyclophosphamide, and rituximab chemotherapy treatment would no longer be demonstrated 11 months after completion of therapy. On the other hand, paronychia was frequently observed by Damasco et al⁸ (63.2% [12/19] of their cases), yet it was not found in our database or the other literature reports we reviewed. Perhaps these differences are due to differences in patient populations and/or available therapies, lack of documentation, or small sample size and limited reports in the literature.

A common question is: Are the nail irregularities caused by the physical symptoms of advanced CTCL or by the underlying disease process in response to the atypical T cells? Erythroderma has been speculated to cause many of the clinical findings of nail abnormalities found in CTCL patients.^2,3 However, Fleming et al¹⁴ described an MF patient who experienced onychomadesis without erythroderma, which suggests that a different mechanism may cause these nail changes. The wide range of nail abnormalities in CTCL can cause problems with diagnosing the specific cause underlying the nail alteration.

To further complicate the issue, numerous therapies for CTCL also may cause nail changes, such as the previously described Beau lines. In 2010, Parmentier et al⁴ reported a patient with nail alterations that had been present for more than 1 year, with 9 of 10 fingernails demonstrating anonychia, onychomadesis, subungual distal hyperkeratosis, and onycholysis. In this case report, the authors were able to exclude phototherapy as the cause of onycholysis (visible separation of the nail plate from the nail bed) and other clinical nail findings in the SS patient based on the onset of nail changes prior to beginning psoralen plus UVA therapy and complete sparing of 1 finger.⁴ The findings in our patient 1, who had no history of psoralen plus UVA therapy at the time the irregular nail findings presented, supports this observation. Total skin electron beam therapy for MF also has been reported to cause temporary nail stasis and thus must be taken into account when considering nail changes in patients with MF/SS.¹⁵

A nail matrix biopsy may provide clues to the definitive cause of the clinically observed nail changes; however, this procedure typically is not performed due to patient concerns of postoperative complications including pain and nail dystrophy.¹⁶ Histopathology features were similar in reported nail biopsies of 2 SS patients.^3,4 Tosti et al³ reported that longitudinal biopsy showed a dense lymphocytic infiltrate of atypical lymphocytes with involuted nuclei and notable epidermotropism. Parmentier et al⁴ reported a longitudinal nail biopsy in an SS patient that presented with atypical lymphocytes, epidermotropism, and Pautrier microabscess formation. Immunostaining showed CD3 positivity within the distal nail matrix, nail bed, and hyponychium. One-third of the cells stained positive for CD4, while the majority stained positive for CD8. Most notably, the skin, nails, and blood showed identical clonal rearrangement of TCRγ.⁴ Nail matrix biopsies in MF patients rarely have been reported in the literature, but those that are available show similar features to those seen in SS patients. Harland et al¹⁷ summarized the findings of 4 case reports of CTCL patients that included nail biopsies by stating, “[a]ll histopathologic findings from nail biopsies showed a dense subepithelial infiltrate of lymphocytes with marked epitheliotropism.” These histopathologic abnormalities are akin to skin biopsies in MF patients, thus providing an essential link to the disease state of MF and the nail abnormalities found within SS patients.

Treatment of the nail problems found within SS is challenging due to limited research. Parmentier et al⁴ noted an SS patient who was treated with topical mechlorethamine applied directly to the nail. In this case, topical mechlorethamine was effective at treating onychomadesis, subungual distal hyperkeratosis, and onycholysis within 6 months.⁴ Another SS patient, who presented with thickening and yellowing of the nail, had reported a proximal nail plate that resolved after chemotherapy. The patient did not survive long enough to note complete improvement of the nail.³ In our study, patient 1 was treated with ciclopirox gel and terbinafine, which did not result in nail improvement. Nail treatments in SS patients have yet to show much improvement and thus need more research and focus in the literature.

Conclusion

Sézary syndrome is a rare CTCL that can present with clinical features that may be mistaken for other diseases. Nail abnormalities in SS patients may be related to fungal involvement, medical therapy, or the underlying disease process of SS. We report one of the largest populations of SS patients with specific reported nail abnormalities, thus expanding the possibilities of nail changes that accompany the disease. Continued research and studies involving SS can provide a better understanding of nail involvement and successful treatment of these clinical findings.

Sézary syndrome (SS) is an advanced leukemic form of cutaneous T-cell lymphoma (CTCL) that is characterized by generalized erythroderma and T-cell leukemia. Skin changes can include erythroderma, keratosis pilaris–like lesions, keratoderma, ectropion, alopecia, and nail changes.¹ Nail changes in SS patients frequently are overlooked and underreported; they vary greatly from patient to patient, and their incidence has not been widely evaluated in the literature.

In this retrospective study, we reviewed medical records from a previously collected CTCL clinic database at the University of Texas MD Anderson Cancer Center (Houston, Texas) and found nail abnormalities in 36 of 83 (43.4%) patients with a diagnosis of SS. Findings for 2 select cases are described in more detail; they were compared to prior case reports from the literature to establish a comprehensive list of nail irregularities that have been associated with SS.

Methods

We examined records from a previously collected CTCL clinic database at the University of Texas MD Anderson Cancer Center. This database was part of an institutional review board–approved protocol to prospectively collect data from patients with CTCL. Our search yielded 83 patients with SS who were seen between 2007 and 2014.

Results

Of the 83 cases reviewed from the CTCL database, 36 (43.4%) SS patients reported at least 1 nail abnormality on the fingernails or toenails. Patients ranged in age from 59 to 85 years and included 27 (75%) men and 9 (25%) women. Nail irregularities noted on physical examination are summarized in Table 1. More than half of the patients presented with nail thickening (58.3% [21/36]), dystrophy (55.6% [20/36]), or yellowing (55.6% [20/36]) of 1 or more nails. Other findings included 15 (41.7%) patients with subungual hyperkeratosis, 3 (8.3%) with Beau lines, and 1 (2.8%) with multiple oil spots consistent with salmon patches. Five (13.9%) patients had only 1 reported nail irregularity, and 1 (2.8%) patient had 6 irregularities. The average number of nail abnormalities per patient was 2.88 (range, 1–6). We selected 2 patients with extensive nail findings who represent the spectrum of nail findings in patients with SS.

Patient 1
A 71-year-old white man presented with a papular rash of 30 years’ duration. The eruption first occurred on the soles of the feet but progressed to generalized erythroderma. He was found to be colonized with methicillin-resistant Staphylococcus aureus. Over the next 9 months, the patient was diagnosed with SS at an outside institution and was treated with cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone, gemcitabine, etoposide, methylprednisolone, cytarabine, cisplatin, topical steroids, and intravenous methotrexate with no apparent improvement. At presentation to our institution, physical examination revealed pruritus; alopecia; generalized lymphadenopathy; erythroderma; and irregular nail findings, including yellowing, thickened fingernails and toenails with subungual debris, and splinter hemorrhage (Figure 1). A thick plaque with perioral distribution as well as erosions on the face and feet were noted. The total body surface area (BSA) affected was 100% (patches, 91%; plaques, 9%).

At diagnosis at our institution, the patient’s white blood cell (WBC) count was 17,800/µL (reference range, 4000–11,000/µL), with 11% Sézary cells noted. Biopsy of a lymph node from the inguinal area indicated T-cell lymphoma with clonal T-cell receptor (TCR) β gene rearrangement. Biopsy of lesional skin in the right groin area showed an atypical T-cell lymphocytic infiltrate with a CD4:CD8 ratio of 2.9:1 and partial loss of CD7 expression, consistent with mycosis fungoides (MF)/SS stage IVA. At presentation to our institution, the WBC count was 12,700/µL with a neutrophil count of 47% (reference range, 42%–66%), lymphocyte count of 36% (reference range, 24%–44%), monocyte count of 4% (reference range, 2%–7%), platelet count of 427,000/µL (reference range, 150,000–350,000/µL), hemoglobin of 9.9 g/dL (reference range, 14.0–17.5 g/dL), and lactate dehydrogenase of 733 U/L (reference range, 135–214 U/L). Lymphocytes were positive for CD2, CD3, CD4, CD5, CD25, CD52, TCRα, TCRβ, and TCR VB17; partial for CD26; and negative for CD7, CD8, and CD57. At follow-up 1 month later, the CD4⁺CD26⁻ T-cell population was 56%, which was consistent with SS T-cell lymphoma.

Skin scrapings from the generalized keratoderma on the patient’s feet were positive for fungal hyphae under potassium hydroxide examination. Nail clippings showed compact keratin with periodic acid–Schiff–positive small yeast forms admixed with bacterial organisms, consistent with onychomycosis. At our institution, the patient received extracorporeal photopheresis, whirlpool therapy (a type of hydrotherapy), steroid wet wraps, and intravenous vancomycin for methicillin-resistant S aureus. He also received bexarotene, levothyroxine sodium, and fenofibrate. After antibiotics and 2 sessions of photopheresis, the total BSA improved from 100% to 33%. The feet and nails were treated with ciclopirox gel and terbinafine, but neither the keratoderma nor the nails improved.

Patient 2
An 84-year-old white man with B-cell chronic lymphocytic leukemia also was diagnosed with SS at an outside institution. One year later, he presented to our institution with mild pruritus and swelling of the lower left leg, which was diagnosed as deep vein thrombosis. There was bilateral scaling of the palms, with fissures present on the left palm. The fingernails showed dystrophy with Beau lines, and the toenails were dystrophic with onycholysis on the bilateral great toes (Figure 2). Patches were noted on most of the body, including the feet, with plaques limited to the hands; the total BSA affected was 80%. Flow cytometry showed an elevated Sézary cell count (CD4⁺CD26⁻) of 4700 cells/µL. Complete blood cell count with differential included a hemoglobin level of 11.4 g/dL, hematocrit level of 35.3% (reference range, 37%–47%), a platelet count of 217,000/µL, and a WBC count of 17,700/µL, of which 29% were neutrophils, 63% were lymphocytes, 6% were monocytes, and 2% were eosinophils. The lactate dehydrogenase level was elevated at 829 U/L. The patient had not been treated for chronic lymphocytic leukemia in the last 11 months due to adverse reactions to rituximab after 2 cycles of fludarabine, cyclophosphamide, and rituximab chemotherapy. First-line therapy for the patient was photopheresis for SS.

Comment

Nail changes are found in many cases of advanced-stage SS but rarely have been reported in the literature. A literature review of PubMed articles indexed for MEDLINE was conducted using the search terms Sézary, nail, onychodystrophy, cutaneous T-cell lymphoma, and CTCL. All results were reviewed for original reported cases of SS with at least 1 reported nail finding. A total of 7 reports^2-8 met these requirements with a total of 43 SS patients with reported nail findings, which are summarized in Tables 2 and 3.

Our findings are generally consistent with those previously described in the literature. Nail thickening, yellowing, subungual hyperkeratosis, dystrophy, and onycholysis are consistently some of the most common nail findings in patients with SS. In 2012, Martin and Duvic⁹ found that 52.9% (45/85) of SS patients with keratoderma on physical examination were positive for dermatophyte hyphae when skin scrapings were done under potassium hydroxide examination, a considerably greater incidence than in the general population (10%–20%). The nail changes seen in our SS patients were identical to those found in dermatophyte infections, including discoloration, subungual debris, nail thickening, onycholysis, and dystrophy.¹⁰ In patient 1, nail clippings were positive for onychomycosis, a common nail condition that is especially prevalent in older or immunocompromised patients.^9,10

Interestingly, findings not observed in the literature included salmon patches and Beau lines. Beau lines are horizontal depressions in the nail plate and often are indicative of temporary interruption of nail growth, such as due to an underlying disease process, severe illness, and/or chemotherapy.^11,12 In our review, patient 2 had clinical findings of Beau lines. Because the average time for fingernail regrowth is 3 to 6 months,¹³ it is reasonable to assume that physical findings associated with fludarabine, cyclophosphamide, and rituximab chemotherapy treatment would no longer be demonstrated 11 months after completion of therapy. On the other hand, paronychia was frequently observed by Damasco et al⁸ (63.2% [12/19] of their cases), yet it was not found in our database or the other literature reports we reviewed. Perhaps these differences are due to differences in patient populations and/or available therapies, lack of documentation, or small sample size and limited reports in the literature.

A common question is: Are the nail irregularities caused by the physical symptoms of advanced CTCL or by the underlying disease process in response to the atypical T cells? Erythroderma has been speculated to cause many of the clinical findings of nail abnormalities found in CTCL patients.^2,3 However, Fleming et al¹⁴ described an MF patient who experienced onychomadesis without erythroderma, which suggests that a different mechanism may cause these nail changes. The wide range of nail abnormalities in CTCL can cause problems with diagnosing the specific cause underlying the nail alteration.

To further complicate the issue, numerous therapies for CTCL also may cause nail changes, such as the previously described Beau lines. In 2010, Parmentier et al⁴ reported a patient with nail alterations that had been present for more than 1 year, with 9 of 10 fingernails demonstrating anonychia, onychomadesis, subungual distal hyperkeratosis, and onycholysis. In this case report, the authors were able to exclude phototherapy as the cause of onycholysis (visible separation of the nail plate from the nail bed) and other clinical nail findings in the SS patient based on the onset of nail changes prior to beginning psoralen plus UVA therapy and complete sparing of 1 finger.⁴ The findings in our patient 1, who had no history of psoralen plus UVA therapy at the time the irregular nail findings presented, supports this observation. Total skin electron beam therapy for MF also has been reported to cause temporary nail stasis and thus must be taken into account when considering nail changes in patients with MF/SS.¹⁵

A nail matrix biopsy may provide clues to the definitive cause of the clinically observed nail changes; however, this procedure typically is not performed due to patient concerns of postoperative complications including pain and nail dystrophy.¹⁶ Histopathology features were similar in reported nail biopsies of 2 SS patients.^3,4 Tosti et al³ reported that longitudinal biopsy showed a dense lymphocytic infiltrate of atypical lymphocytes with involuted nuclei and notable epidermotropism. Parmentier et al⁴ reported a longitudinal nail biopsy in an SS patient that presented with atypical lymphocytes, epidermotropism, and Pautrier microabscess formation. Immunostaining showed CD3 positivity within the distal nail matrix, nail bed, and hyponychium. One-third of the cells stained positive for CD4, while the majority stained positive for CD8. Most notably, the skin, nails, and blood showed identical clonal rearrangement of TCRγ.⁴ Nail matrix biopsies in MF patients rarely have been reported in the literature, but those that are available show similar features to those seen in SS patients. Harland et al¹⁷ summarized the findings of 4 case reports of CTCL patients that included nail biopsies by stating, “[a]ll histopathologic findings from nail biopsies showed a dense subepithelial infiltrate of lymphocytes with marked epitheliotropism.” These histopathologic abnormalities are akin to skin biopsies in MF patients, thus providing an essential link to the disease state of MF and the nail abnormalities found within SS patients.

Treatment of the nail problems found within SS is challenging due to limited research. Parmentier et al⁴ noted an SS patient who was treated with topical mechlorethamine applied directly to the nail. In this case, topical mechlorethamine was effective at treating onychomadesis, subungual distal hyperkeratosis, and onycholysis within 6 months.⁴ Another SS patient, who presented with thickening and yellowing of the nail, had reported a proximal nail plate that resolved after chemotherapy. The patient did not survive long enough to note complete improvement of the nail.³ In our study, patient 1 was treated with ciclopirox gel and terbinafine, which did not result in nail improvement. Nail treatments in SS patients have yet to show much improvement and thus need more research and focus in the literature.

Conclusion

Sézary syndrome is a rare CTCL that can present with clinical features that may be mistaken for other diseases. Nail abnormalities in SS patients may be related to fungal involvement, medical therapy, or the underlying disease process of SS. We report one of the largest populations of SS patients with specific reported nail abnormalities, thus expanding the possibilities of nail changes that accompany the disease. Continued research and studies involving SS can provide a better understanding of nail involvement and successful treatment of these clinical findings.

Sézary syndrome (SS) is an advanced leukemic form of cutaneous T-cell lymphoma (CTCL) that is characterized by generalized erythroderma and T-cell leukemia. Skin changes can include erythroderma, keratosis pilaris–like lesions, keratoderma, ectropion, alopecia, and nail changes.¹ Nail changes in SS patients frequently are overlooked and underreported; they vary greatly from patient to patient, and their incidence has not been widely evaluated in the literature.

In this retrospective study, we reviewed medical records from a previously collected CTCL clinic database at the University of Texas MD Anderson Cancer Center (Houston, Texas) and found nail abnormalities in 36 of 83 (43.4%) patients with a diagnosis of SS. Findings for 2 select cases are described in more detail; they were compared to prior case reports from the literature to establish a comprehensive list of nail irregularities that have been associated with SS.

Methods

We examined records from a previously collected CTCL clinic database at the University of Texas MD Anderson Cancer Center. This database was part of an institutional review board–approved protocol to prospectively collect data from patients with CTCL. Our search yielded 83 patients with SS who were seen between 2007 and 2014.

Results

Of the 83 cases reviewed from the CTCL database, 36 (43.4%) SS patients reported at least 1 nail abnormality on the fingernails or toenails. Patients ranged in age from 59 to 85 years and included 27 (75%) men and 9 (25%) women. Nail irregularities noted on physical examination are summarized in Table 1. More than half of the patients presented with nail thickening (58.3% [21/36]), dystrophy (55.6% [20/36]), or yellowing (55.6% [20/36]) of 1 or more nails. Other findings included 15 (41.7%) patients with subungual hyperkeratosis, 3 (8.3%) with Beau lines, and 1 (2.8%) with multiple oil spots consistent with salmon patches. Five (13.9%) patients had only 1 reported nail irregularity, and 1 (2.8%) patient had 6 irregularities. The average number of nail abnormalities per patient was 2.88 (range, 1–6). We selected 2 patients with extensive nail findings who represent the spectrum of nail findings in patients with SS.

Patient 1
A 71-year-old white man presented with a papular rash of 30 years’ duration. The eruption first occurred on the soles of the feet but progressed to generalized erythroderma. He was found to be colonized with methicillin-resistant Staphylococcus aureus. Over the next 9 months, the patient was diagnosed with SS at an outside institution and was treated with cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone, gemcitabine, etoposide, methylprednisolone, cytarabine, cisplatin, topical steroids, and intravenous methotrexate with no apparent improvement. At presentation to our institution, physical examination revealed pruritus; alopecia; generalized lymphadenopathy; erythroderma; and irregular nail findings, including yellowing, thickened fingernails and toenails with subungual debris, and splinter hemorrhage (Figure 1). A thick plaque with perioral distribution as well as erosions on the face and feet were noted. The total body surface area (BSA) affected was 100% (patches, 91%; plaques, 9%).

At diagnosis at our institution, the patient’s white blood cell (WBC) count was 17,800/µL (reference range, 4000–11,000/µL), with 11% Sézary cells noted. Biopsy of a lymph node from the inguinal area indicated T-cell lymphoma with clonal T-cell receptor (TCR) β gene rearrangement. Biopsy of lesional skin in the right groin area showed an atypical T-cell lymphocytic infiltrate with a CD4:CD8 ratio of 2.9:1 and partial loss of CD7 expression, consistent with mycosis fungoides (MF)/SS stage IVA. At presentation to our institution, the WBC count was 12,700/µL with a neutrophil count of 47% (reference range, 42%–66%), lymphocyte count of 36% (reference range, 24%–44%), monocyte count of 4% (reference range, 2%–7%), platelet count of 427,000/µL (reference range, 150,000–350,000/µL), hemoglobin of 9.9 g/dL (reference range, 14.0–17.5 g/dL), and lactate dehydrogenase of 733 U/L (reference range, 135–214 U/L). Lymphocytes were positive for CD2, CD3, CD4, CD5, CD25, CD52, TCRα, TCRβ, and TCR VB17; partial for CD26; and negative for CD7, CD8, and CD57. At follow-up 1 month later, the CD4⁺CD26⁻ T-cell population was 56%, which was consistent with SS T-cell lymphoma.

Skin scrapings from the generalized keratoderma on the patient’s feet were positive for fungal hyphae under potassium hydroxide examination. Nail clippings showed compact keratin with periodic acid–Schiff–positive small yeast forms admixed with bacterial organisms, consistent with onychomycosis. At our institution, the patient received extracorporeal photopheresis, whirlpool therapy (a type of hydrotherapy), steroid wet wraps, and intravenous vancomycin for methicillin-resistant S aureus. He also received bexarotene, levothyroxine sodium, and fenofibrate. After antibiotics and 2 sessions of photopheresis, the total BSA improved from 100% to 33%. The feet and nails were treated with ciclopirox gel and terbinafine, but neither the keratoderma nor the nails improved.

Patient 2
An 84-year-old white man with B-cell chronic lymphocytic leukemia also was diagnosed with SS at an outside institution. One year later, he presented to our institution with mild pruritus and swelling of the lower left leg, which was diagnosed as deep vein thrombosis. There was bilateral scaling of the palms, with fissures present on the left palm. The fingernails showed dystrophy with Beau lines, and the toenails were dystrophic with onycholysis on the bilateral great toes (Figure 2). Patches were noted on most of the body, including the feet, with plaques limited to the hands; the total BSA affected was 80%. Flow cytometry showed an elevated Sézary cell count (CD4⁺CD26⁻) of 4700 cells/µL. Complete blood cell count with differential included a hemoglobin level of 11.4 g/dL, hematocrit level of 35.3% (reference range, 37%–47%), a platelet count of 217,000/µL, and a WBC count of 17,700/µL, of which 29% were neutrophils, 63% were lymphocytes, 6% were monocytes, and 2% were eosinophils. The lactate dehydrogenase level was elevated at 829 U/L. The patient had not been treated for chronic lymphocytic leukemia in the last 11 months due to adverse reactions to rituximab after 2 cycles of fludarabine, cyclophosphamide, and rituximab chemotherapy. First-line therapy for the patient was photopheresis for SS.

Comment

Nail changes are found in many cases of advanced-stage SS but rarely have been reported in the literature. A literature review of PubMed articles indexed for MEDLINE was conducted using the search terms Sézary, nail, onychodystrophy, cutaneous T-cell lymphoma, and CTCL. All results were reviewed for original reported cases of SS with at least 1 reported nail finding. A total of 7 reports^2-8 met these requirements with a total of 43 SS patients with reported nail findings, which are summarized in Tables 2 and 3.

Our findings are generally consistent with those previously described in the literature. Nail thickening, yellowing, subungual hyperkeratosis, dystrophy, and onycholysis are consistently some of the most common nail findings in patients with SS. In 2012, Martin and Duvic⁹ found that 52.9% (45/85) of SS patients with keratoderma on physical examination were positive for dermatophyte hyphae when skin scrapings were done under potassium hydroxide examination, a considerably greater incidence than in the general population (10%–20%). The nail changes seen in our SS patients were identical to those found in dermatophyte infections, including discoloration, subungual debris, nail thickening, onycholysis, and dystrophy.¹⁰ In patient 1, nail clippings were positive for onychomycosis, a common nail condition that is especially prevalent in older or immunocompromised patients.^9,10

Interestingly, findings not observed in the literature included salmon patches and Beau lines. Beau lines are horizontal depressions in the nail plate and often are indicative of temporary interruption of nail growth, such as due to an underlying disease process, severe illness, and/or chemotherapy.^11,12 In our review, patient 2 had clinical findings of Beau lines. Because the average time for fingernail regrowth is 3 to 6 months,¹³ it is reasonable to assume that physical findings associated with fludarabine, cyclophosphamide, and rituximab chemotherapy treatment would no longer be demonstrated 11 months after completion of therapy. On the other hand, paronychia was frequently observed by Damasco et al⁸ (63.2% [12/19] of their cases), yet it was not found in our database or the other literature reports we reviewed. Perhaps these differences are due to differences in patient populations and/or available therapies, lack of documentation, or small sample size and limited reports in the literature.

A common question is: Are the nail irregularities caused by the physical symptoms of advanced CTCL or by the underlying disease process in response to the atypical T cells? Erythroderma has been speculated to cause many of the clinical findings of nail abnormalities found in CTCL patients.^2,3 However, Fleming et al¹⁴ described an MF patient who experienced onychomadesis without erythroderma, which suggests that a different mechanism may cause these nail changes. The wide range of nail abnormalities in CTCL can cause problems with diagnosing the specific cause underlying the nail alteration.

To further complicate the issue, numerous therapies for CTCL also may cause nail changes, such as the previously described Beau lines. In 2010, Parmentier et al⁴ reported a patient with nail alterations that had been present for more than 1 year, with 9 of 10 fingernails demonstrating anonychia, onychomadesis, subungual distal hyperkeratosis, and onycholysis. In this case report, the authors were able to exclude phototherapy as the cause of onycholysis (visible separation of the nail plate from the nail bed) and other clinical nail findings in the SS patient based on the onset of nail changes prior to beginning psoralen plus UVA therapy and complete sparing of 1 finger.⁴ The findings in our patient 1, who had no history of psoralen plus UVA therapy at the time the irregular nail findings presented, supports this observation. Total skin electron beam therapy for MF also has been reported to cause temporary nail stasis and thus must be taken into account when considering nail changes in patients with MF/SS.¹⁵

A nail matrix biopsy may provide clues to the definitive cause of the clinically observed nail changes; however, this procedure typically is not performed due to patient concerns of postoperative complications including pain and nail dystrophy.¹⁶ Histopathology features were similar in reported nail biopsies of 2 SS patients.^3,4 Tosti et al³ reported that longitudinal biopsy showed a dense lymphocytic infiltrate of atypical lymphocytes with involuted nuclei and notable epidermotropism. Parmentier et al⁴ reported a longitudinal nail biopsy in an SS patient that presented with atypical lymphocytes, epidermotropism, and Pautrier microabscess formation. Immunostaining showed CD3 positivity within the distal nail matrix, nail bed, and hyponychium. One-third of the cells stained positive for CD4, while the majority stained positive for CD8. Most notably, the skin, nails, and blood showed identical clonal rearrangement of TCRγ.⁴ Nail matrix biopsies in MF patients rarely have been reported in the literature, but those that are available show similar features to those seen in SS patients. Harland et al¹⁷ summarized the findings of 4 case reports of CTCL patients that included nail biopsies by stating, “[a]ll histopathologic findings from nail biopsies showed a dense subepithelial infiltrate of lymphocytes with marked epitheliotropism.” These histopathologic abnormalities are akin to skin biopsies in MF patients, thus providing an essential link to the disease state of MF and the nail abnormalities found within SS patients.

Treatment of the nail problems found within SS is challenging due to limited research. Parmentier et al⁴ noted an SS patient who was treated with topical mechlorethamine applied directly to the nail. In this case, topical mechlorethamine was effective at treating onychomadesis, subungual distal hyperkeratosis, and onycholysis within 6 months.⁴ Another SS patient, who presented with thickening and yellowing of the nail, had reported a proximal nail plate that resolved after chemotherapy. The patient did not survive long enough to note complete improvement of the nail.³ In our study, patient 1 was treated with ciclopirox gel and terbinafine, which did not result in nail improvement. Nail treatments in SS patients have yet to show much improvement and thus need more research and focus in the literature.

Conclusion

Sézary syndrome is a rare CTCL that can present with clinical features that may be mistaken for other diseases. Nail abnormalities in SS patients may be related to fungal involvement, medical therapy, or the underlying disease process of SS. We report one of the largest populations of SS patients with specific reported nail abnormalities, thus expanding the possibilities of nail changes that accompany the disease. Continued research and studies involving SS can provide a better understanding of nail involvement and successful treatment of these clinical findings.

To the Editor:

A 25-year-old woman with no notable medical history was admitted to the hospital for suspected Stevens-Johnson syndrome (SJS). The patient was started on amoxicillin 7 days prior to the skin eruption for prophylaxis before removal of an intrauterine device. On the day of admission, she reported ocular discomfort, dysphagia, and dysuria. She developed erythema of the conjunctivae, face, chest, and proximal upper extremities, as well as erosions of the vermilion lips. She presented to the local emergency department and was transferred to our institution for urgent dermatologic consultation. On physical examination by the dermatology service, the patient had erythematous macules coalescing into patches with overlying flaccid bullae, some denuded, involving the face, chest, abdomen, back (Figure 1), bilateral upper extremities, bilateral thighs, and labia majora and minora. Additionally, she had conjunctivitis, superficial erosions of the vermilion lips, and tense bullae of the palms and soles. On palpation of the flaccid bullae, the Asboe-Hansen sign was elicited (Figure 2 and video). A shave biopsy of the newly elicited bullae was performed. Pathology showed a subepidermal bulla with confluent necrosis of the epidermis and minimal inflammatory infiltrate. An additional shave biopsy of perilesional skin was obtained for direct immunofluorescence, which was negative for IgG, C3, IgM, and IgA. Based on the clinical presentation involving more than 30% of the patient’s body surface area (BSA) and the pathology findings, a diagnosis of toxic epidermal necrolysis (TEN) was made. The patient remained in the intensive care unit with a multidisciplinary team consisting of dermatology, ophthalmology, gynecology, gastroenterology, and the general surgery burn group. Following treatment with intravenous immunoglobulin, systemic corticosteroids, and aggressive wound care, the patient made a full recovery.

Vidyard Video

Toxic epidermal necrolysis is a rare, acute, life-threatening mucocutaneous disease within a spectrum of adverse cutaneous drug reactions. The estimated worldwide incidence of TEN is 0.4 to 1.9 per million individuals annually.¹ Toxic epidermal necrolysis is clinically characterized by diffuse exfoliation of the skin and mucosae with flaccid bullae. These clinical features are a consequence of extensive keratinocyte death, leading to dermoepidermal junction dissociation. Commonly, there is a prodrome of fever, pharyngitis, and painful skin preceding the diffuse erythema and sloughing of skin and mucous membranes. Lesions typically first appear on the trunk and then follow a centrifugal spread, often sparing the distal aspects of the arms and legs.

Toxic epidermal necrolysis is part of a continuous spectrum with SJS. Less than 10% BSA involvement is considered SJS, 10% to 30% BSA involvement is SJS/TEN overlap, and more than 30% BSA detachment is TEN. Stevens-Johnson syndrome can progress to TEN. In TEN, the distribution of cutaneous lesions is more confluent, and mucosal involvement is more severe.² The differential diagnosis may include staphylococcal scalded skin syndrome, drug-induced linear IgA bullous dermatosis, severe acute graft-vs-host disease, drug reaction with eosinophilia and systemic symptoms, and invasive fungal dermatitis. An accurate diagnosis of TEN is imperative, as the management and morbidity of these diseases are vastly different. Toxic epidermal necrolysis has an estimated mortality rate of 25% to 30%, with sepsis leading to multiorgan failure being the most common cause of death.³

Although the pathophysiology of TEN has yet to be fully elucidated, it is thought to be a T cell–mediated process with CD8⁺ cells acting as the primary means of keratinocyte death. An estimated 80% to 95% of cases are due to drug reactions.³ The medications that are most commonly associated with TEN include allopurinol, antibiotics, nonsteroidal anti-inflammatory drugs, and anticonvulsants. Symptoms typically begin 7 to 21 days after starting the drug. Less commonly, Mycoplasma pneumoniae, dengue virus, cytomegalovirus, and contrast medium have been reported as inciting factors for TEN.²

The diagnosis of TEN is established by correlating clinical features with a histopathologic examination obtained from a lesional skin biopsy. The classic cutaneous features of TEN begin as erythematous, flesh-colored, dusky to violaceous macules and/or morbilliform or targetoid lesions. These early lesions have the tendency to coalesce. The cutaneous findings will eventually progress into flaccid bullae, diffuse epidermal sloughing, and full-thickness skin necrosis.^2,3 The evolution of skin lesions may be rapid or may take several days to develop. On palpation, the Nikolsky (lateral shearing of epidermis with minimal pressure) and Asboe-Hansen sign will be positive in patients with SJS/TEN, demonstrating that the associated blisters are flaccid and may be displaced peripherally.⁴ For an accurate diagnosis, the biopsy must contain full-thickness epidermis. It is imperative to choose a biopsy site from an acute blister, as old lesions of other diseases, such as erythema multiforme, will eventually become necrotic and mimic the histopathologic appearance of SJS/TEN, potentially leading to an incorrect diagnosis.⁴ Full-thickness epidermal necrosis has a high sensitivity but low specificity for TEN.³ The histologic features of TEN vary depending on the stage of the disease. Classic histologic findings include satellite necrosis of keratinocytes followed by full-thickness necrosis of keratinocytes and perivascular lymphoid infiltrates. The stratum corneum retains its original structure.⁴

The Asboe-Hansen sign, also known as the bulla spread sign, was originally described in 1960 as a diagnostic sign for pemphigus vulgaris.⁵ A positive Asboe-Hansen sign demonstrates the ability to enlarge a bulla in the lateral direction by applying perpendicular mechanical pressure to the roof of an intact bulla. The bulla is extended to adjacent nonblistered skin.⁶ A positive sign demonstrates decreased adhesion between keratinocytes or between the basal epidermal cells and the dermal connective tissue.⁵ In addition to pemphigus vulgaris, the Asboe-Hansen sign may be positive in TEN and SJS, as well as other diseases affecting the dermoepidermal junction including pemphigus foliaceus, pemphigus vegetans, and bullous pemphigoid. Asboe-Hansen⁵ made the argument that a fresh bulla should be biopsied if histopathologic diagnosis is necessary, as older bullae may exhibit epithelial cell regeneration and disturb an accurate diagnosis.

Accurate and early diagnosis of TEN is imperative, as prognosis is strongly correlated with the speed at which the offending drug is discontinued and appropriate medical treatment is initiated. Prompt withdrawal of the offending drug has been reported to reduce the risk for morbidity by 30% per day.⁷ Although classically associated with the pemphigus group of diseases, the Asboe-Hansen sign is of diagnostic value to the pathologist in diagnosing TEN by reproducing the same microscopic appearance of a fresh spontaneous blister. Due to the notable morbidity and mortality in SJS and TEN, the Asboe-Hansen sign should be attempted for the site of a lesional biopsy, as an accurate diagnosis relies on clinicopathologic correlation.

To the Editor:

A 25-year-old woman with no notable medical history was admitted to the hospital for suspected Stevens-Johnson syndrome (SJS). The patient was started on amoxicillin 7 days prior to the skin eruption for prophylaxis before removal of an intrauterine device. On the day of admission, she reported ocular discomfort, dysphagia, and dysuria. She developed erythema of the conjunctivae, face, chest, and proximal upper extremities, as well as erosions of the vermilion lips. She presented to the local emergency department and was transferred to our institution for urgent dermatologic consultation. On physical examination by the dermatology service, the patient had erythematous macules coalescing into patches with overlying flaccid bullae, some denuded, involving the face, chest, abdomen, back (Figure 1), bilateral upper extremities, bilateral thighs, and labia majora and minora. Additionally, she had conjunctivitis, superficial erosions of the vermilion lips, and tense bullae of the palms and soles. On palpation of the flaccid bullae, the Asboe-Hansen sign was elicited (Figure 2 and video). A shave biopsy of the newly elicited bullae was performed. Pathology showed a subepidermal bulla with confluent necrosis of the epidermis and minimal inflammatory infiltrate. An additional shave biopsy of perilesional skin was obtained for direct immunofluorescence, which was negative for IgG, C3, IgM, and IgA. Based on the clinical presentation involving more than 30% of the patient’s body surface area (BSA) and the pathology findings, a diagnosis of toxic epidermal necrolysis (TEN) was made. The patient remained in the intensive care unit with a multidisciplinary team consisting of dermatology, ophthalmology, gynecology, gastroenterology, and the general surgery burn group. Following treatment with intravenous immunoglobulin, systemic corticosteroids, and aggressive wound care, the patient made a full recovery.

Vidyard Video

Toxic epidermal necrolysis is a rare, acute, life-threatening mucocutaneous disease within a spectrum of adverse cutaneous drug reactions. The estimated worldwide incidence of TEN is 0.4 to 1.9 per million individuals annually.¹ Toxic epidermal necrolysis is clinically characterized by diffuse exfoliation of the skin and mucosae with flaccid bullae. These clinical features are a consequence of extensive keratinocyte death, leading to dermoepidermal junction dissociation. Commonly, there is a prodrome of fever, pharyngitis, and painful skin preceding the diffuse erythema and sloughing of skin and mucous membranes. Lesions typically first appear on the trunk and then follow a centrifugal spread, often sparing the distal aspects of the arms and legs.

Toxic epidermal necrolysis is part of a continuous spectrum with SJS. Less than 10% BSA involvement is considered SJS, 10% to 30% BSA involvement is SJS/TEN overlap, and more than 30% BSA detachment is TEN. Stevens-Johnson syndrome can progress to TEN. In TEN, the distribution of cutaneous lesions is more confluent, and mucosal involvement is more severe.² The differential diagnosis may include staphylococcal scalded skin syndrome, drug-induced linear IgA bullous dermatosis, severe acute graft-vs-host disease, drug reaction with eosinophilia and systemic symptoms, and invasive fungal dermatitis. An accurate diagnosis of TEN is imperative, as the management and morbidity of these diseases are vastly different. Toxic epidermal necrolysis has an estimated mortality rate of 25% to 30%, with sepsis leading to multiorgan failure being the most common cause of death.³

Although the pathophysiology of TEN has yet to be fully elucidated, it is thought to be a T cell–mediated process with CD8⁺ cells acting as the primary means of keratinocyte death. An estimated 80% to 95% of cases are due to drug reactions.³ The medications that are most commonly associated with TEN include allopurinol, antibiotics, nonsteroidal anti-inflammatory drugs, and anticonvulsants. Symptoms typically begin 7 to 21 days after starting the drug. Less commonly, Mycoplasma pneumoniae, dengue virus, cytomegalovirus, and contrast medium have been reported as inciting factors for TEN.²

The diagnosis of TEN is established by correlating clinical features with a histopathologic examination obtained from a lesional skin biopsy. The classic cutaneous features of TEN begin as erythematous, flesh-colored, dusky to violaceous macules and/or morbilliform or targetoid lesions. These early lesions have the tendency to coalesce. The cutaneous findings will eventually progress into flaccid bullae, diffuse epidermal sloughing, and full-thickness skin necrosis.^2,3 The evolution of skin lesions may be rapid or may take several days to develop. On palpation, the Nikolsky (lateral shearing of epidermis with minimal pressure) and Asboe-Hansen sign will be positive in patients with SJS/TEN, demonstrating that the associated blisters are flaccid and may be displaced peripherally.⁴ For an accurate diagnosis, the biopsy must contain full-thickness epidermis. It is imperative to choose a biopsy site from an acute blister, as old lesions of other diseases, such as erythema multiforme, will eventually become necrotic and mimic the histopathologic appearance of SJS/TEN, potentially leading to an incorrect diagnosis.⁴ Full-thickness epidermal necrosis has a high sensitivity but low specificity for TEN.³ The histologic features of TEN vary depending on the stage of the disease. Classic histologic findings include satellite necrosis of keratinocytes followed by full-thickness necrosis of keratinocytes and perivascular lymphoid infiltrates. The stratum corneum retains its original structure.⁴

The Asboe-Hansen sign, also known as the bulla spread sign, was originally described in 1960 as a diagnostic sign for pemphigus vulgaris.⁵ A positive Asboe-Hansen sign demonstrates the ability to enlarge a bulla in the lateral direction by applying perpendicular mechanical pressure to the roof of an intact bulla. The bulla is extended to adjacent nonblistered skin.⁶ A positive sign demonstrates decreased adhesion between keratinocytes or between the basal epidermal cells and the dermal connective tissue.⁵ In addition to pemphigus vulgaris, the Asboe-Hansen sign may be positive in TEN and SJS, as well as other diseases affecting the dermoepidermal junction including pemphigus foliaceus, pemphigus vegetans, and bullous pemphigoid. Asboe-Hansen⁵ made the argument that a fresh bulla should be biopsied if histopathologic diagnosis is necessary, as older bullae may exhibit epithelial cell regeneration and disturb an accurate diagnosis.

Accurate and early diagnosis of TEN is imperative, as prognosis is strongly correlated with the speed at which the offending drug is discontinued and appropriate medical treatment is initiated. Prompt withdrawal of the offending drug has been reported to reduce the risk for morbidity by 30% per day.⁷ Although classically associated with the pemphigus group of diseases, the Asboe-Hansen sign is of diagnostic value to the pathologist in diagnosing TEN by reproducing the same microscopic appearance of a fresh spontaneous blister. Due to the notable morbidity and mortality in SJS and TEN, the Asboe-Hansen sign should be attempted for the site of a lesional biopsy, as an accurate diagnosis relies on clinicopathologic correlation.

To the Editor:

A 25-year-old woman with no notable medical history was admitted to the hospital for suspected Stevens-Johnson syndrome (SJS). The patient was started on amoxicillin 7 days prior to the skin eruption for prophylaxis before removal of an intrauterine device. On the day of admission, she reported ocular discomfort, dysphagia, and dysuria. She developed erythema of the conjunctivae, face, chest, and proximal upper extremities, as well as erosions of the vermilion lips. She presented to the local emergency department and was transferred to our institution for urgent dermatologic consultation. On physical examination by the dermatology service, the patient had erythematous macules coalescing into patches with overlying flaccid bullae, some denuded, involving the face, chest, abdomen, back (Figure 1), bilateral upper extremities, bilateral thighs, and labia majora and minora. Additionally, she had conjunctivitis, superficial erosions of the vermilion lips, and tense bullae of the palms and soles. On palpation of the flaccid bullae, the Asboe-Hansen sign was elicited (Figure 2 and video). A shave biopsy of the newly elicited bullae was performed. Pathology showed a subepidermal bulla with confluent necrosis of the epidermis and minimal inflammatory infiltrate. An additional shave biopsy of perilesional skin was obtained for direct immunofluorescence, which was negative for IgG, C3, IgM, and IgA. Based on the clinical presentation involving more than 30% of the patient’s body surface area (BSA) and the pathology findings, a diagnosis of toxic epidermal necrolysis (TEN) was made. The patient remained in the intensive care unit with a multidisciplinary team consisting of dermatology, ophthalmology, gynecology, gastroenterology, and the general surgery burn group. Following treatment with intravenous immunoglobulin, systemic corticosteroids, and aggressive wound care, the patient made a full recovery.

Vidyard Video

Toxic epidermal necrolysis is a rare, acute, life-threatening mucocutaneous disease within a spectrum of adverse cutaneous drug reactions. The estimated worldwide incidence of TEN is 0.4 to 1.9 per million individuals annually.¹ Toxic epidermal necrolysis is clinically characterized by diffuse exfoliation of the skin and mucosae with flaccid bullae. These clinical features are a consequence of extensive keratinocyte death, leading to dermoepidermal junction dissociation. Commonly, there is a prodrome of fever, pharyngitis, and painful skin preceding the diffuse erythema and sloughing of skin and mucous membranes. Lesions typically first appear on the trunk and then follow a centrifugal spread, often sparing the distal aspects of the arms and legs.

Toxic epidermal necrolysis is part of a continuous spectrum with SJS. Less than 10% BSA involvement is considered SJS, 10% to 30% BSA involvement is SJS/TEN overlap, and more than 30% BSA detachment is TEN. Stevens-Johnson syndrome can progress to TEN. In TEN, the distribution of cutaneous lesions is more confluent, and mucosal involvement is more severe.² The differential diagnosis may include staphylococcal scalded skin syndrome, drug-induced linear IgA bullous dermatosis, severe acute graft-vs-host disease, drug reaction with eosinophilia and systemic symptoms, and invasive fungal dermatitis. An accurate diagnosis of TEN is imperative, as the management and morbidity of these diseases are vastly different. Toxic epidermal necrolysis has an estimated mortality rate of 25% to 30%, with sepsis leading to multiorgan failure being the most common cause of death.³

Although the pathophysiology of TEN has yet to be fully elucidated, it is thought to be a T cell–mediated process with CD8⁺ cells acting as the primary means of keratinocyte death. An estimated 80% to 95% of cases are due to drug reactions.³ The medications that are most commonly associated with TEN include allopurinol, antibiotics, nonsteroidal anti-inflammatory drugs, and anticonvulsants. Symptoms typically begin 7 to 21 days after starting the drug. Less commonly, Mycoplasma pneumoniae, dengue virus, cytomegalovirus, and contrast medium have been reported as inciting factors for TEN.²

The diagnosis of TEN is established by correlating clinical features with a histopathologic examination obtained from a lesional skin biopsy. The classic cutaneous features of TEN begin as erythematous, flesh-colored, dusky to violaceous macules and/or morbilliform or targetoid lesions. These early lesions have the tendency to coalesce. The cutaneous findings will eventually progress into flaccid bullae, diffuse epidermal sloughing, and full-thickness skin necrosis.^2,3 The evolution of skin lesions may be rapid or may take several days to develop. On palpation, the Nikolsky (lateral shearing of epidermis with minimal pressure) and Asboe-Hansen sign will be positive in patients with SJS/TEN, demonstrating that the associated blisters are flaccid and may be displaced peripherally.⁴ For an accurate diagnosis, the biopsy must contain full-thickness epidermis. It is imperative to choose a biopsy site from an acute blister, as old lesions of other diseases, such as erythema multiforme, will eventually become necrotic and mimic the histopathologic appearance of SJS/TEN, potentially leading to an incorrect diagnosis.⁴ Full-thickness epidermal necrosis has a high sensitivity but low specificity for TEN.³ The histologic features of TEN vary depending on the stage of the disease. Classic histologic findings include satellite necrosis of keratinocytes followed by full-thickness necrosis of keratinocytes and perivascular lymphoid infiltrates. The stratum corneum retains its original structure.⁴

The Asboe-Hansen sign, also known as the bulla spread sign, was originally described in 1960 as a diagnostic sign for pemphigus vulgaris.⁵ A positive Asboe-Hansen sign demonstrates the ability to enlarge a bulla in the lateral direction by applying perpendicular mechanical pressure to the roof of an intact bulla. The bulla is extended to adjacent nonblistered skin.⁶ A positive sign demonstrates decreased adhesion between keratinocytes or between the basal epidermal cells and the dermal connective tissue.⁵ In addition to pemphigus vulgaris, the Asboe-Hansen sign may be positive in TEN and SJS, as well as other diseases affecting the dermoepidermal junction including pemphigus foliaceus, pemphigus vegetans, and bullous pemphigoid. Asboe-Hansen⁵ made the argument that a fresh bulla should be biopsied if histopathologic diagnosis is necessary, as older bullae may exhibit epithelial cell regeneration and disturb an accurate diagnosis.

Accurate and early diagnosis of TEN is imperative, as prognosis is strongly correlated with the speed at which the offending drug is discontinued and appropriate medical treatment is initiated. Prompt withdrawal of the offending drug has been reported to reduce the risk for morbidity by 30% per day.⁷ Although classically associated with the pemphigus group of diseases, the Asboe-Hansen sign is of diagnostic value to the pathologist in diagnosing TEN by reproducing the same microscopic appearance of a fresh spontaneous blister. Due to the notable morbidity and mortality in SJS and TEN, the Asboe-Hansen sign should be attempted for the site of a lesional biopsy, as an accurate diagnosis relies on clinicopathologic correlation.

SAN FRANCISCO – Artificial intelligence (AI) is using computer technology to solve particular kinds of medical problems, Sushovan Guha, MD, PhD, AGAF, chair, division of gastroenterology, University of Arizona, Phoenix, said in an interview at the AGA Tech Summit, sponsored by the AGA Center for GI Innovation and Technology.

Vidyard Video

Computers are good at doing many processes in a short period of time and executing repetitive tasks with no errors, whereas humans tend to introduce errors after many repetitions. Using algorithms by which physicians assess and diagnose colonic lesions, computer software can learn the criteria that diagnose adenomas and assist in the process of diagnosis, Dr. Guha said.

Computers are also ideal for managing and analyzing large amounts of data – this ability has so far been used to personalize cancer treatment – and is now being used to suggest the best treatment and predict remission in patients with inflammatory bowel disease. AI can use anatomical data combined with endoscopy to predict GI bleeding so that physicians can target therapy. Dr. Guha predicts that there will be an “explosion” of applications of AI in gastroenterology in the next 5-10 years.

SAN FRANCISCO – Artificial intelligence (AI) is using computer technology to solve particular kinds of medical problems, Sushovan Guha, MD, PhD, AGAF, chair, division of gastroenterology, University of Arizona, Phoenix, said in an interview at the AGA Tech Summit, sponsored by the AGA Center for GI Innovation and Technology.

Vidyard Video

Computers are good at doing many processes in a short period of time and executing repetitive tasks with no errors, whereas humans tend to introduce errors after many repetitions. Using algorithms by which physicians assess and diagnose colonic lesions, computer software can learn the criteria that diagnose adenomas and assist in the process of diagnosis, Dr. Guha said.

Computers are also ideal for managing and analyzing large amounts of data – this ability has so far been used to personalize cancer treatment – and is now being used to suggest the best treatment and predict remission in patients with inflammatory bowel disease. AI can use anatomical data combined with endoscopy to predict GI bleeding so that physicians can target therapy. Dr. Guha predicts that there will be an “explosion” of applications of AI in gastroenterology in the next 5-10 years.

SAN FRANCISCO – Artificial intelligence (AI) is using computer technology to solve particular kinds of medical problems, Sushovan Guha, MD, PhD, AGAF, chair, division of gastroenterology, University of Arizona, Phoenix, said in an interview at the AGA Tech Summit, sponsored by the AGA Center for GI Innovation and Technology.

Vidyard Video

Computers are good at doing many processes in a short period of time and executing repetitive tasks with no errors, whereas humans tend to introduce errors after many repetitions. Using algorithms by which physicians assess and diagnose colonic lesions, computer software can learn the criteria that diagnose adenomas and assist in the process of diagnosis, Dr. Guha said.

Computers are also ideal for managing and analyzing large amounts of data – this ability has so far been used to personalize cancer treatment – and is now being used to suggest the best treatment and predict remission in patients with inflammatory bowel disease. AI can use anatomical data combined with endoscopy to predict GI bleeding so that physicians can target therapy. Dr. Guha predicts that there will be an “explosion” of applications of AI in gastroenterology in the next 5-10 years.

To the Editor:

Lichen amyloidosis (LA) classically presents as a pruritic, hyperkeratotic, papular eruption localized to the pretibial surface of the legs.¹ Nonpruritic and generalized variants have been reported but are rare.² Although it is the most common subtype of primary localized cutaneous amyloidosis, LA is a benign condition but is difficult to eradicate.¹ The precise pathophysiology is poorly understood, but chronic frictional irritation is closely associated with the eruption. We present a nongeneralized case of LA in an atypical location.

A healthy 30-year-old woman presented with an intermittent itchy rash on the elbows and knees of 2 years’ duration. The patient was first diagnosed with lichen simplex chronicus (LSC) and initially responded well to treatment with fluocinonide ointment 0.05%. Nearly 2 years after the initial presentation, she developed recurrent symptoms and sought further treatment. She reported frequent scratching in association with episodes of anxiety. Examination revealed numerous 1- to 3-mm, flesh-colored to light brown, monomorphic, dome-shaped papules over the extensor surfaces of the bilateral arms and left pretibial surface (Figure 1).

^4-6

The possibility remains that this patient first presented with LSC 2 years prior and secondarily developed LA due to chronic trauma. Indeed, LA has been proposed as a variant of LSC. In both conditions, scratching seems to be the most important factor in the development of lesions. It has been proposed that treatment should primarily focus on the amelioration of pruritus.⁵

Five percent to 10% of cases of LA have been found to have some form of upper extremity involvement.⁷ However, these cases typically are associated with a generalized presentation involving the trunk and arms.^2,7 Our patient had no evidence of disease elsewhere. When evaluating a localized, pruritic, monomorphic, papular eruption on the extensor surfaces of the arms, LA may be an important consideration.

To the Editor:

Lichen amyloidosis (LA) classically presents as a pruritic, hyperkeratotic, papular eruption localized to the pretibial surface of the legs.¹ Nonpruritic and generalized variants have been reported but are rare.² Although it is the most common subtype of primary localized cutaneous amyloidosis, LA is a benign condition but is difficult to eradicate.¹ The precise pathophysiology is poorly understood, but chronic frictional irritation is closely associated with the eruption. We present a nongeneralized case of LA in an atypical location.

A healthy 30-year-old woman presented with an intermittent itchy rash on the elbows and knees of 2 years’ duration. The patient was first diagnosed with lichen simplex chronicus (LSC) and initially responded well to treatment with fluocinonide ointment 0.05%. Nearly 2 years after the initial presentation, she developed recurrent symptoms and sought further treatment. She reported frequent scratching in association with episodes of anxiety. Examination revealed numerous 1- to 3-mm, flesh-colored to light brown, monomorphic, dome-shaped papules over the extensor surfaces of the bilateral arms and left pretibial surface (Figure 1).

^4-6

The possibility remains that this patient first presented with LSC 2 years prior and secondarily developed LA due to chronic trauma. Indeed, LA has been proposed as a variant of LSC. In both conditions, scratching seems to be the most important factor in the development of lesions. It has been proposed that treatment should primarily focus on the amelioration of pruritus.⁵

Five percent to 10% of cases of LA have been found to have some form of upper extremity involvement.⁷ However, these cases typically are associated with a generalized presentation involving the trunk and arms.^2,7 Our patient had no evidence of disease elsewhere. When evaluating a localized, pruritic, monomorphic, papular eruption on the extensor surfaces of the arms, LA may be an important consideration.

To the Editor:

Lichen amyloidosis (LA) classically presents as a pruritic, hyperkeratotic, papular eruption localized to the pretibial surface of the legs.¹ Nonpruritic and generalized variants have been reported but are rare.² Although it is the most common subtype of primary localized cutaneous amyloidosis, LA is a benign condition but is difficult to eradicate.¹ The precise pathophysiology is poorly understood, but chronic frictional irritation is closely associated with the eruption. We present a nongeneralized case of LA in an atypical location.

A healthy 30-year-old woman presented with an intermittent itchy rash on the elbows and knees of 2 years’ duration. The patient was first diagnosed with lichen simplex chronicus (LSC) and initially responded well to treatment with fluocinonide ointment 0.05%. Nearly 2 years after the initial presentation, she developed recurrent symptoms and sought further treatment. She reported frequent scratching in association with episodes of anxiety. Examination revealed numerous 1- to 3-mm, flesh-colored to light brown, monomorphic, dome-shaped papules over the extensor surfaces of the bilateral arms and left pretibial surface (Figure 1).

^4-6

The possibility remains that this patient first presented with LSC 2 years prior and secondarily developed LA due to chronic trauma. Indeed, LA has been proposed as a variant of LSC. In both conditions, scratching seems to be the most important factor in the development of lesions. It has been proposed that treatment should primarily focus on the amelioration of pruritus.⁵

Five percent to 10% of cases of LA have been found to have some form of upper extremity involvement.⁷ However, these cases typically are associated with a generalized presentation involving the trunk and arms.^2,7 Our patient had no evidence of disease elsewhere. When evaluating a localized, pruritic, monomorphic, papular eruption on the extensor surfaces of the arms, LA may be an important consideration.

Who’s responsible for the rising cost of insulin? Manufacturers and pharmacy benefit managers pointed their fingers at each other on April 10 at a congressional hearing.

Courtesy Oversight and Investigations Subcommittee

In response, Democrats and Republicans on the House Energy & Commerce Subcommittee on Oversight and Investigations said they might just take matters into their own hands.

Rebates and discounts are the drivers, according to leaders from three insulin manufacturers.

Mike Mason, a senior vice president of Eli Lilly & Co., was put on the defensive immediately by Subcommittee Chairman Diana DeGette (D-Colo.), who asked him to justify the increases in list prices during the last 10 years.

“Seventy-five percent of our list price is paid for rebates and discounts to secure access so people have affordable access,” Mr. Mason said.

He was cut off in his response as Rep. DeGette pressed further: “So that’s what’s making the price go up and up.”

To which Mr. Mason responded, “$210 of a vial of Humalog is paid for discounts and rebates.” It was noted during the hearing that a vial has a list price of $275.

Doug Langa, an executive vice president at Novo Nordisk, agreed. “There is significant demand for rebates.”

Kathleen Tregoning, an executive vice president at Sanofi, added that, as part of setting the list price, “we have to look at the dynamics of the supply chain, including the rebates.”

Leaders of several pharmacy benefit managers disagreed.

Rep. DeGette asked Thomas M. Moriarty, an executive vice president and general counsel at CVS Health whether he thought rebates were forcing manufacturers to raise list prices. His response? “I do not, no.”

Amy Bricker, a senior vice president at Express Scripts concurred. “I have no idea why list prices are high, and it’s not a result of rebates.”

Sumit Dutta, MD, a senior vice president and chief medical officer at OptumRx, added that there have been list prices rising double digits in nonrebated drugs, in generics where a manufacturer buys out the market to create a monopoly.

“We can’t see a correlation just when rebates raise list prices,” Dr. Dutta said.

While the PBMs denied the rebate system played any role in the setting of list prices, they were firm in maintaining secrecy in rebating process.

When asked by Rep. John Sarbanes (D-Md.) whether the public should be able to track the list price and see the rebates, the net prices, and the savings that are passed along to the consumer, Ms. Bricker said “we don’t believe so.”

She continued: “The reason I’m able to get the discounts that I can from the manufacturer is because it is confidential.”

And while Ms. Tregoning offered support for full transparency in every facet of the supply chain, Ms. Bricker did not. “It will hurt the consumer, Congressman, because prices will be held high.”

“I’m not buying it,” Rep. Sarbanes replied. “I think a system has been built that allows for gaming to go on and you’ve all got your talking points.”

Rep. Buddy Carter (R-Ga.), Congress’ only pharmacist, does not on the committee but was allowed to participate in the hearing. He shared with his colleagues stories of customers leaving prescriptions behind because of cost.

He asked Mr. Langa whether he thought PBM consolidation played a role in driving up rebates and list prices, to which Mr. Langa said, “I think it was a factor.”

Rep. Carter offering a sarcastic congratulations to the panel.

“You’ve done something here today that we’ve been trying to do in Congress for the 4 years and 3 months I’ve been here, and that is to create bipartisanship.”

He then cautioned PBM leaders on the panel that the status quo “is going to end. ... I have seen what you have done with the PBMs” and all the various fees that have been created over time and said that Congress will make sure rebate reform will happen, specifically for Medicare and Medicaid. But he added, “we are not going to stop there.”

During the hearing, the manufacturers, while being not completely committal, suggested that list prices could in fact come down if rebates and discounts were done away with, while the PBMs would not commit to flat administrative fees as opposed to current fees that are based on list prices.

Rep. DeGette said that work will continue until all parties come up with a viable solution. Action “is not optional and it is going to happen.”

[email protected]

Who’s responsible for the rising cost of insulin? Manufacturers and pharmacy benefit managers pointed their fingers at each other on April 10 at a congressional hearing.

Courtesy Oversight and Investigations Subcommittee

In response, Democrats and Republicans on the House Energy & Commerce Subcommittee on Oversight and Investigations said they might just take matters into their own hands.

Rebates and discounts are the drivers, according to leaders from three insulin manufacturers.

Mike Mason, a senior vice president of Eli Lilly & Co., was put on the defensive immediately by Subcommittee Chairman Diana DeGette (D-Colo.), who asked him to justify the increases in list prices during the last 10 years.

“Seventy-five percent of our list price is paid for rebates and discounts to secure access so people have affordable access,” Mr. Mason said.

He was cut off in his response as Rep. DeGette pressed further: “So that’s what’s making the price go up and up.”

To which Mr. Mason responded, “$210 of a vial of Humalog is paid for discounts and rebates.” It was noted during the hearing that a vial has a list price of $275.

Doug Langa, an executive vice president at Novo Nordisk, agreed. “There is significant demand for rebates.”

Kathleen Tregoning, an executive vice president at Sanofi, added that, as part of setting the list price, “we have to look at the dynamics of the supply chain, including the rebates.”

Leaders of several pharmacy benefit managers disagreed.

Rep. DeGette asked Thomas M. Moriarty, an executive vice president and general counsel at CVS Health whether he thought rebates were forcing manufacturers to raise list prices. His response? “I do not, no.”

Amy Bricker, a senior vice president at Express Scripts concurred. “I have no idea why list prices are high, and it’s not a result of rebates.”

Sumit Dutta, MD, a senior vice president and chief medical officer at OptumRx, added that there have been list prices rising double digits in nonrebated drugs, in generics where a manufacturer buys out the market to create a monopoly.

“We can’t see a correlation just when rebates raise list prices,” Dr. Dutta said.

While the PBMs denied the rebate system played any role in the setting of list prices, they were firm in maintaining secrecy in rebating process.

When asked by Rep. John Sarbanes (D-Md.) whether the public should be able to track the list price and see the rebates, the net prices, and the savings that are passed along to the consumer, Ms. Bricker said “we don’t believe so.”

She continued: “The reason I’m able to get the discounts that I can from the manufacturer is because it is confidential.”

And while Ms. Tregoning offered support for full transparency in every facet of the supply chain, Ms. Bricker did not. “It will hurt the consumer, Congressman, because prices will be held high.”

“I’m not buying it,” Rep. Sarbanes replied. “I think a system has been built that allows for gaming to go on and you’ve all got your talking points.”

Rep. Buddy Carter (R-Ga.), Congress’ only pharmacist, does not on the committee but was allowed to participate in the hearing. He shared with his colleagues stories of customers leaving prescriptions behind because of cost.

He asked Mr. Langa whether he thought PBM consolidation played a role in driving up rebates and list prices, to which Mr. Langa said, “I think it was a factor.”

Rep. Carter offering a sarcastic congratulations to the panel.

“You’ve done something here today that we’ve been trying to do in Congress for the 4 years and 3 months I’ve been here, and that is to create bipartisanship.”

He then cautioned PBM leaders on the panel that the status quo “is going to end. ... I have seen what you have done with the PBMs” and all the various fees that have been created over time and said that Congress will make sure rebate reform will happen, specifically for Medicare and Medicaid. But he added, “we are not going to stop there.”

During the hearing, the manufacturers, while being not completely committal, suggested that list prices could in fact come down if rebates and discounts were done away with, while the PBMs would not commit to flat administrative fees as opposed to current fees that are based on list prices.

Rep. DeGette said that work will continue until all parties come up with a viable solution. Action “is not optional and it is going to happen.”

[email protected]

Who’s responsible for the rising cost of insulin? Manufacturers and pharmacy benefit managers pointed their fingers at each other on April 10 at a congressional hearing.

Courtesy Oversight and Investigations Subcommittee

In response, Democrats and Republicans on the House Energy & Commerce Subcommittee on Oversight and Investigations said they might just take matters into their own hands.

Rebates and discounts are the drivers, according to leaders from three insulin manufacturers.

Mike Mason, a senior vice president of Eli Lilly & Co., was put on the defensive immediately by Subcommittee Chairman Diana DeGette (D-Colo.), who asked him to justify the increases in list prices during the last 10 years.

“Seventy-five percent of our list price is paid for rebates and discounts to secure access so people have affordable access,” Mr. Mason said.

He was cut off in his response as Rep. DeGette pressed further: “So that’s what’s making the price go up and up.”

To which Mr. Mason responded, “$210 of a vial of Humalog is paid for discounts and rebates.” It was noted during the hearing that a vial has a list price of $275.

Doug Langa, an executive vice president at Novo Nordisk, agreed. “There is significant demand for rebates.”

Kathleen Tregoning, an executive vice president at Sanofi, added that, as part of setting the list price, “we have to look at the dynamics of the supply chain, including the rebates.”

Leaders of several pharmacy benefit managers disagreed.

Rep. DeGette asked Thomas M. Moriarty, an executive vice president and general counsel at CVS Health whether he thought rebates were forcing manufacturers to raise list prices. His response? “I do not, no.”

Amy Bricker, a senior vice president at Express Scripts concurred. “I have no idea why list prices are high, and it’s not a result of rebates.”

Sumit Dutta, MD, a senior vice president and chief medical officer at OptumRx, added that there have been list prices rising double digits in nonrebated drugs, in generics where a manufacturer buys out the market to create a monopoly.

“We can’t see a correlation just when rebates raise list prices,” Dr. Dutta said.

While the PBMs denied the rebate system played any role in the setting of list prices, they were firm in maintaining secrecy in rebating process.

When asked by Rep. John Sarbanes (D-Md.) whether the public should be able to track the list price and see the rebates, the net prices, and the savings that are passed along to the consumer, Ms. Bricker said “we don’t believe so.”

She continued: “The reason I’m able to get the discounts that I can from the manufacturer is because it is confidential.”

And while Ms. Tregoning offered support for full transparency in every facet of the supply chain, Ms. Bricker did not. “It will hurt the consumer, Congressman, because prices will be held high.”

“I’m not buying it,” Rep. Sarbanes replied. “I think a system has been built that allows for gaming to go on and you’ve all got your talking points.”

Rep. Buddy Carter (R-Ga.), Congress’ only pharmacist, does not on the committee but was allowed to participate in the hearing. He shared with his colleagues stories of customers leaving prescriptions behind because of cost.

He asked Mr. Langa whether he thought PBM consolidation played a role in driving up rebates and list prices, to which Mr. Langa said, “I think it was a factor.”

Rep. Carter offering a sarcastic congratulations to the panel.

“You’ve done something here today that we’ve been trying to do in Congress for the 4 years and 3 months I’ve been here, and that is to create bipartisanship.”

He then cautioned PBM leaders on the panel that the status quo “is going to end. ... I have seen what you have done with the PBMs” and all the various fees that have been created over time and said that Congress will make sure rebate reform will happen, specifically for Medicare and Medicaid. But he added, “we are not going to stop there.”

During the hearing, the manufacturers, while being not completely committal, suggested that list prices could in fact come down if rebates and discounts were done away with, while the PBMs would not commit to flat administrative fees as opposed to current fees that are based on list prices.

Rep. DeGette said that work will continue until all parties come up with a viable solution. Action “is not optional and it is going to happen.”

[email protected]

GENEVA – Radiogenomic MRI signatures may be able to identify anaplastic lymphoma kinase (ALK)–positive brain metastases in non–small cell lung cancer (NSCLC), offering a minimally invasive option that could allow for initiation of treatment while waiting for molecular results, according to investigators.

Will Pass/MDedge News

In the future, artificial intelligence may be able to detect these imaging patterns, allowing for rapid and accurate mutation subtyping, reported lead author Shweta Wadhwa, MD, of Tata Memorial Centre in Mumbai, India, who presented the findings at the European Lung Cancer Conference.

“Radiogenomics is a concept used to associate genetic information with medical images,” Dr. Wadhwa explained at the meeting presented by the European Society for Medical Oncology. “It creates imaging biomarkers noninvasively without using biopsy. … The aim of my study was to analyze certain MRI data genomic parameters and correlate with the ALK mutation status.”

Dr. Wadhwa and her colleagues retrospectively analyzed data from 75 patients with ALK-positive NSCLC who underwent multiparametric MRI at the time of diagnosis. Univariate logistic regression analysis was conducted to look for associations between ALK mutation status and various clinical factors, including sex, age, smoking, histology, TNM stage, and imaging characteristics.

Out of 75 patients, 46 were ALK positive and 29 were ALK negative. Analysis showed that ALK positivity was associated with a variety of lesion morphology characteristics. ALK-positive lesions more often exhibited a fuzzy and infiltrative T2w border with hypointense peripheral solid rim, compared with ALK-negative lesions, which frequently had a well-defined T2w border with no solid rim (P less than .001). On T1w, most ALK-positive lesions were heterogeneous, whereas ALK-negative lesions were predominantly hypointense (P less than .001). Diffusion-weighted images showed that ALK-positive lesions often had peripheral restriction of the solid rim, compared with ALK-negative lesions, which were associated with central restriction (P = .001). MRI also revealed that about half of ALK-positive patients (54.3%) had meningeal involvement, compared with just 17.2% of ALK-negative patients (P = .02). ALK positivity was also associated with younger age and lack of smoking history. Considering these findings, Dr. Wadhwa concluded that “radiogenomics has a potential role in personalized management of ALK-positive NSCLC brain metastases.”

In an interview, Dr. Wadhwa provided more insight regarding the clinical need for this technology. “We have to wait for 10 days [for molecular diagnostic results], and ALK is usually aggressive disease, so if we wait for 10 days, patients can undergo rapid progression.”

Dr. Wadhwa noted that these results are similar to that of her colleague, Abhishek Mahajan, MD, who recently published results showing potential for radiogenomic detection of epidermal growth factor receptor (EGFR) status. According to Dr. Wadhwa, the two investigators plan to build on their collective findings in an effort to automate radiogenomic detection of NSCLC mutation subtypes.

“My upcoming project with my coinvestigator is to take a bigger sample,” Dr. Wadhwa said. “We will be further generalizing [this process] to all patients in a prospective study. We will also be sending this to the University of Pennsylvania for automatic brain segmentation.” Dr. Wadhwa estimated that adding automation will provide an accuracy rate of around 90%.

“We will train the computer accordingly,” Dr. Wadhwa said, “and then the computer will tell us, yes, this is ALK positive, this is EGFR positive.”

The investigators reported no external study funding and reported no conflicts of interest.

SOURCE: Wadhwa S et al. ELCC 2019, Abstract 55O.

GENEVA – Radiogenomic MRI signatures may be able to identify anaplastic lymphoma kinase (ALK)–positive brain metastases in non–small cell lung cancer (NSCLC), offering a minimally invasive option that could allow for initiation of treatment while waiting for molecular results, according to investigators.

Will Pass/MDedge News

In the future, artificial intelligence may be able to detect these imaging patterns, allowing for rapid and accurate mutation subtyping, reported lead author Shweta Wadhwa, MD, of Tata Memorial Centre in Mumbai, India, who presented the findings at the European Lung Cancer Conference.

“Radiogenomics is a concept used to associate genetic information with medical images,” Dr. Wadhwa explained at the meeting presented by the European Society for Medical Oncology. “It creates imaging biomarkers noninvasively without using biopsy. … The aim of my study was to analyze certain MRI data genomic parameters and correlate with the ALK mutation status.”

Dr. Wadhwa and her colleagues retrospectively analyzed data from 75 patients with ALK-positive NSCLC who underwent multiparametric MRI at the time of diagnosis. Univariate logistic regression analysis was conducted to look for associations between ALK mutation status and various clinical factors, including sex, age, smoking, histology, TNM stage, and imaging characteristics.

Out of 75 patients, 46 were ALK positive and 29 were ALK negative. Analysis showed that ALK positivity was associated with a variety of lesion morphology characteristics. ALK-positive lesions more often exhibited a fuzzy and infiltrative T2w border with hypointense peripheral solid rim, compared with ALK-negative lesions, which frequently had a well-defined T2w border with no solid rim (P less than .001). On T1w, most ALK-positive lesions were heterogeneous, whereas ALK-negative lesions were predominantly hypointense (P less than .001). Diffusion-weighted images showed that ALK-positive lesions often had peripheral restriction of the solid rim, compared with ALK-negative lesions, which were associated with central restriction (P = .001). MRI also revealed that about half of ALK-positive patients (54.3%) had meningeal involvement, compared with just 17.2% of ALK-negative patients (P = .02). ALK positivity was also associated with younger age and lack of smoking history. Considering these findings, Dr. Wadhwa concluded that “radiogenomics has a potential role in personalized management of ALK-positive NSCLC brain metastases.”

In an interview, Dr. Wadhwa provided more insight regarding the clinical need for this technology. “We have to wait for 10 days [for molecular diagnostic results], and ALK is usually aggressive disease, so if we wait for 10 days, patients can undergo rapid progression.”

Dr. Wadhwa noted that these results are similar to that of her colleague, Abhishek Mahajan, MD, who recently published results showing potential for radiogenomic detection of epidermal growth factor receptor (EGFR) status. According to Dr. Wadhwa, the two investigators plan to build on their collective findings in an effort to automate radiogenomic detection of NSCLC mutation subtypes.

“My upcoming project with my coinvestigator is to take a bigger sample,” Dr. Wadhwa said. “We will be further generalizing [this process] to all patients in a prospective study. We will also be sending this to the University of Pennsylvania for automatic brain segmentation.” Dr. Wadhwa estimated that adding automation will provide an accuracy rate of around 90%.

“We will train the computer accordingly,” Dr. Wadhwa said, “and then the computer will tell us, yes, this is ALK positive, this is EGFR positive.”

The investigators reported no external study funding and reported no conflicts of interest.

SOURCE: Wadhwa S et al. ELCC 2019, Abstract 55O.

GENEVA – Radiogenomic MRI signatures may be able to identify anaplastic lymphoma kinase (ALK)–positive brain metastases in non–small cell lung cancer (NSCLC), offering a minimally invasive option that could allow for initiation of treatment while waiting for molecular results, according to investigators.

Will Pass/MDedge News

In the future, artificial intelligence may be able to detect these imaging patterns, allowing for rapid and accurate mutation subtyping, reported lead author Shweta Wadhwa, MD, of Tata Memorial Centre in Mumbai, India, who presented the findings at the European Lung Cancer Conference.

“Radiogenomics is a concept used to associate genetic information with medical images,” Dr. Wadhwa explained at the meeting presented by the European Society for Medical Oncology. “It creates imaging biomarkers noninvasively without using biopsy. … The aim of my study was to analyze certain MRI data genomic parameters and correlate with the ALK mutation status.”

Dr. Wadhwa and her colleagues retrospectively analyzed data from 75 patients with ALK-positive NSCLC who underwent multiparametric MRI at the time of diagnosis. Univariate logistic regression analysis was conducted to look for associations between ALK mutation status and various clinical factors, including sex, age, smoking, histology, TNM stage, and imaging characteristics.

Out of 75 patients, 46 were ALK positive and 29 were ALK negative. Analysis showed that ALK positivity was associated with a variety of lesion morphology characteristics. ALK-positive lesions more often exhibited a fuzzy and infiltrative T2w border with hypointense peripheral solid rim, compared with ALK-negative lesions, which frequently had a well-defined T2w border with no solid rim (P less than .001). On T1w, most ALK-positive lesions were heterogeneous, whereas ALK-negative lesions were predominantly hypointense (P less than .001). Diffusion-weighted images showed that ALK-positive lesions often had peripheral restriction of the solid rim, compared with ALK-negative lesions, which were associated with central restriction (P = .001). MRI also revealed that about half of ALK-positive patients (54.3%) had meningeal involvement, compared with just 17.2% of ALK-negative patients (P = .02). ALK positivity was also associated with younger age and lack of smoking history. Considering these findings, Dr. Wadhwa concluded that “radiogenomics has a potential role in personalized management of ALK-positive NSCLC brain metastases.”

In an interview, Dr. Wadhwa provided more insight regarding the clinical need for this technology. “We have to wait for 10 days [for molecular diagnostic results], and ALK is usually aggressive disease, so if we wait for 10 days, patients can undergo rapid progression.”

Dr. Wadhwa noted that these results are similar to that of her colleague, Abhishek Mahajan, MD, who recently published results showing potential for radiogenomic detection of epidermal growth factor receptor (EGFR) status. According to Dr. Wadhwa, the two investigators plan to build on their collective findings in an effort to automate radiogenomic detection of NSCLC mutation subtypes.

“My upcoming project with my coinvestigator is to take a bigger sample,” Dr. Wadhwa said. “We will be further generalizing [this process] to all patients in a prospective study. We will also be sending this to the University of Pennsylvania for automatic brain segmentation.” Dr. Wadhwa estimated that adding automation will provide an accuracy rate of around 90%.

“We will train the computer accordingly,” Dr. Wadhwa said, “and then the computer will tell us, yes, this is ALK positive, this is EGFR positive.”

The investigators reported no external study funding and reported no conflicts of interest.

SOURCE: Wadhwa S et al. ELCC 2019, Abstract 55O.

GENEVA – For lung lesion biopsy, electromagnetic navigation bronchoscopy (ENB) offers high navigational success with a relatively low rate of pneumothorax, according to European data from the international NAVIGATE study.

Will Pass/MDedge News

In addition to lung lesion biopsy, ENB can facilitate concurrent lymph node sampling and fiducial placement during a single anesthetic event, reported lead author Kelvin Lau, MD, chief of thoracic surgery at Barts Thorax Centre in London, and his colleagues. According to Dr. Lau, who presented at the European Lung Cancer Conference, the findings from this European cohort add weight to previously published data from the NAVIGATE trial, which aims to demonstrate real-world use of ENB.

“The outcomes show that [ENB] is very safe in terms of pneumothorax rate, despite the fact that many of these patients were challenging and actually were turned down by the percutaneous radiologist before they came to us,” Dr. Lau said at the meeting, presented by the European Society for Medical Oncology.

Out of 1,200 patients enrolled in the NAVIGATE trial in the United States and Europe, the present 1-month interim analysis showed experiences with 175 patients treated at eight European centers. Anyone undergoing navigational bronchoscopy was eligible. The primary outcome was pneumothorax rate and the secondary outcome was diagnostic yield.

Data analysis showed that lesions were most frequently in the upper lobe (62.6%) and in the peripheral third of the lung (72.7%), the latter of which is beyond the reach of a conventional bronchoscope. In two out of three patients (66.8%), a bronchus sign was present, which “means that the bronchoscope runs straight into the lesion, and theoretically means it’s easier to access,” Dr. Lau said. Almost all patients had ENB for lung biopsy (99.4%), while in a small minority (8.0%), ENB was used for fiducial marking. The median total procedure time was 43.5 minutes, of which 32.9 minutes were spent navigating and sampling with ENB.

The ENB-related pneumothorax rate was 7.4%, although a slightly lower percentage, 5.1%, required intervention or hospitalization. According to the ENB-related Common Terminology Criteria for Adverse Events, 2.3% of patients had grade 2 or higher bronchopulmonary hemorrhage and 0.6% of patients had grade 4 or higher respiratory failure. Although the secondary endpoint, diagnostic yield, was not met because of inadequate follow-up time, the navigational success rate, defined as access to the intended lung lesion, was 96.6%, which offers some sense of efficacy.

“The purpose of this study is to show that [ENB] is very safe,” Dr. Lau said in an interview. “And the numbers are significantly better than historic CT-guided biopsy data.”

Considering the choice between ENB and CT-guided biopsy, invited discussant Anne-Marie Dingemans, MD, of Maastricht University, the Netherlands, offered a different viewpoint.

Will Pass/MDedge News

“CT-guided biopsies are low cost ... and the sensitivity is very, very high,” Dr. Dingemans said. “In good hands, with a good radiologist, you have a high chance that you will have a good diagnosis of the nodules.” She also noted that a bronchus sign does not impact efficacy.

“I’m very into CT-guided biopsies,” Dr. Dingemans continued, noting that the radiologist at her treatment center takes biopsies with a 10-gauge large-core needle. With this technique, Dr. Dingemans reported a 5.7% pneumothorax rate, which is comparable with the present NAVIGATE data.

However, Dr. Lau contested this figure.

“The pneumothorax rates [for CT-guided biopsy] in larger studies have always been about 20% to 40%,” Dr. Lau said. “You can’t compare large overall practice in a pragmatic study capturing everyone versus one single center. The truth is, most centers will have a 20% pneumothorax rate.”

Dr. Lau added that patient experiences are likely to be better with ENB than with CT-guided percutaneous biopsy.

“To me, patient comfort for biopsy is essential,” Dr. Lau said. “Having a needle stuck into your chest – it’s very uncomfortable. I’ve had patients who’ve come to me after they had a percutaneous biopsy and who for some reason needed a re-biopsy ... those patients almost always wish they had navigational bronchoscopy the first time because there would be no pain for them.”

When asked about capital cost concerns surrounding ENB, Dr. Lau suggested that the benefits outweigh the costs.

“The most expensive procedure is the one you have to do again,” Dr. Lau said. “So what we do is put a brush in, and a needle, and a biopsy, and hopefully, one of those three, if not all three, gets tissue, and we can do that with navigational bronchoscopy because there is one channel down. You can’t repeatedly stick needles into patients. By definition, you can’t throw three needle jabs, because you will get a 90% pneumothorax rate. And that’s the beauty of navigational bronchoscopy as well, because in the NAVIGATE series, a number of patients, about 10%, had multiple lesions biopsied.” Furthermore, Dr. Lau noted, percutaneous biopsy is “almost never” performed bilaterally, for fear of collapsing both lungs, but this is not the case with ENB. “We’ve done it on patients who have one lung,” he said.

Dr. Lau predicted that costs of ENB will come down with time. “Because of the number of products increasing, the price will drop,” he said.

Concluding the interview, Dr. Lau offered a summarizing message: “If you want to give the patient the safe option, you should do [ENB], and when it becomes more popular, the price will fall,” he said.

Medtronic funded the study. The investigators reported financial relationships with Olympus, Ambu, PulmonX, Boston Scientific, and others.

SOURCE: Lau et al. ELCC 2019. Abstract 68O.

GENEVA – For lung lesion biopsy, electromagnetic navigation bronchoscopy (ENB) offers high navigational success with a relatively low rate of pneumothorax, according to European data from the international NAVIGATE study.

Will Pass/MDedge News

In addition to lung lesion biopsy, ENB can facilitate concurrent lymph node sampling and fiducial placement during a single anesthetic event, reported lead author Kelvin Lau, MD, chief of thoracic surgery at Barts Thorax Centre in London, and his colleagues. According to Dr. Lau, who presented at the European Lung Cancer Conference, the findings from this European cohort add weight to previously published data from the NAVIGATE trial, which aims to demonstrate real-world use of ENB.

“The outcomes show that [ENB] is very safe in terms of pneumothorax rate, despite the fact that many of these patients were challenging and actually were turned down by the percutaneous radiologist before they came to us,” Dr. Lau said at the meeting, presented by the European Society for Medical Oncology.

Out of 1,200 patients enrolled in the NAVIGATE trial in the United States and Europe, the present 1-month interim analysis showed experiences with 175 patients treated at eight European centers. Anyone undergoing navigational bronchoscopy was eligible. The primary outcome was pneumothorax rate and the secondary outcome was diagnostic yield.

Data analysis showed that lesions were most frequently in the upper lobe (62.6%) and in the peripheral third of the lung (72.7%), the latter of which is beyond the reach of a conventional bronchoscope. In two out of three patients (66.8%), a bronchus sign was present, which “means that the bronchoscope runs straight into the lesion, and theoretically means it’s easier to access,” Dr. Lau said. Almost all patients had ENB for lung biopsy (99.4%), while in a small minority (8.0%), ENB was used for fiducial marking. The median total procedure time was 43.5 minutes, of which 32.9 minutes were spent navigating and sampling with ENB.

The ENB-related pneumothorax rate was 7.4%, although a slightly lower percentage, 5.1%, required intervention or hospitalization. According to the ENB-related Common Terminology Criteria for Adverse Events, 2.3% of patients had grade 2 or higher bronchopulmonary hemorrhage and 0.6% of patients had grade 4 or higher respiratory failure. Although the secondary endpoint, diagnostic yield, was not met because of inadequate follow-up time, the navigational success rate, defined as access to the intended lung lesion, was 96.6%, which offers some sense of efficacy.

“The purpose of this study is to show that [ENB] is very safe,” Dr. Lau said in an interview. “And the numbers are significantly better than historic CT-guided biopsy data.”

Considering the choice between ENB and CT-guided biopsy, invited discussant Anne-Marie Dingemans, MD, of Maastricht University, the Netherlands, offered a different viewpoint.

Will Pass/MDedge News

“CT-guided biopsies are low cost ... and the sensitivity is very, very high,” Dr. Dingemans said. “In good hands, with a good radiologist, you have a high chance that you will have a good diagnosis of the nodules.” She also noted that a bronchus sign does not impact efficacy.

“I’m very into CT-guided biopsies,” Dr. Dingemans continued, noting that the radiologist at her treatment center takes biopsies with a 10-gauge large-core needle. With this technique, Dr. Dingemans reported a 5.7% pneumothorax rate, which is comparable with the present NAVIGATE data.

However, Dr. Lau contested this figure.

“The pneumothorax rates [for CT-guided biopsy] in larger studies have always been about 20% to 40%,” Dr. Lau said. “You can’t compare large overall practice in a pragmatic study capturing everyone versus one single center. The truth is, most centers will have a 20% pneumothorax rate.”

Dr. Lau added that patient experiences are likely to be better with ENB than with CT-guided percutaneous biopsy.

“To me, patient comfort for biopsy is essential,” Dr. Lau said. “Having a needle stuck into your chest – it’s very uncomfortable. I’ve had patients who’ve come to me after they had a percutaneous biopsy and who for some reason needed a re-biopsy ... those patients almost always wish they had navigational bronchoscopy the first time because there would be no pain for them.”

When asked about capital cost concerns surrounding ENB, Dr. Lau suggested that the benefits outweigh the costs.

“The most expensive procedure is the one you have to do again,” Dr. Lau said. “So what we do is put a brush in, and a needle, and a biopsy, and hopefully, one of those three, if not all three, gets tissue, and we can do that with navigational bronchoscopy because there is one channel down. You can’t repeatedly stick needles into patients. By definition, you can’t throw three needle jabs, because you will get a 90% pneumothorax rate. And that’s the beauty of navigational bronchoscopy as well, because in the NAVIGATE series, a number of patients, about 10%, had multiple lesions biopsied.” Furthermore, Dr. Lau noted, percutaneous biopsy is “almost never” performed bilaterally, for fear of collapsing both lungs, but this is not the case with ENB. “We’ve done it on patients who have one lung,” he said.

Dr. Lau predicted that costs of ENB will come down with time. “Because of the number of products increasing, the price will drop,” he said.

Concluding the interview, Dr. Lau offered a summarizing message: “If you want to give the patient the safe option, you should do [ENB], and when it becomes more popular, the price will fall,” he said.

Medtronic funded the study. The investigators reported financial relationships with Olympus, Ambu, PulmonX, Boston Scientific, and others.

SOURCE: Lau et al. ELCC 2019. Abstract 68O.

GENEVA – For lung lesion biopsy, electromagnetic navigation bronchoscopy (ENB) offers high navigational success with a relatively low rate of pneumothorax, according to European data from the international NAVIGATE study.

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In addition to lung lesion biopsy, ENB can facilitate concurrent lymph node sampling and fiducial placement during a single anesthetic event, reported lead author Kelvin Lau, MD, chief of thoracic surgery at Barts Thorax Centre in London, and his colleagues. According to Dr. Lau, who presented at the European Lung Cancer Conference, the findings from this European cohort add weight to previously published data from the NAVIGATE trial, which aims to demonstrate real-world use of ENB.

“The outcomes show that [ENB] is very safe in terms of pneumothorax rate, despite the fact that many of these patients were challenging and actually were turned down by the percutaneous radiologist before they came to us,” Dr. Lau said at the meeting, presented by the European Society for Medical Oncology.

Out of 1,200 patients enrolled in the NAVIGATE trial in the United States and Europe, the present 1-month interim analysis showed experiences with 175 patients treated at eight European centers. Anyone undergoing navigational bronchoscopy was eligible. The primary outcome was pneumothorax rate and the secondary outcome was diagnostic yield.

Data analysis showed that lesions were most frequently in the upper lobe (62.6%) and in the peripheral third of the lung (72.7%), the latter of which is beyond the reach of a conventional bronchoscope. In two out of three patients (66.8%), a bronchus sign was present, which “means that the bronchoscope runs straight into the lesion, and theoretically means it’s easier to access,” Dr. Lau said. Almost all patients had ENB for lung biopsy (99.4%), while in a small minority (8.0%), ENB was used for fiducial marking. The median total procedure time was 43.5 minutes, of which 32.9 minutes were spent navigating and sampling with ENB.

The ENB-related pneumothorax rate was 7.4%, although a slightly lower percentage, 5.1%, required intervention or hospitalization. According to the ENB-related Common Terminology Criteria for Adverse Events, 2.3% of patients had grade 2 or higher bronchopulmonary hemorrhage and 0.6% of patients had grade 4 or higher respiratory failure. Although the secondary endpoint, diagnostic yield, was not met because of inadequate follow-up time, the navigational success rate, defined as access to the intended lung lesion, was 96.6%, which offers some sense of efficacy.

“The purpose of this study is to show that [ENB] is very safe,” Dr. Lau said in an interview. “And the numbers are significantly better than historic CT-guided biopsy data.”

Considering the choice between ENB and CT-guided biopsy, invited discussant Anne-Marie Dingemans, MD, of Maastricht University, the Netherlands, offered a different viewpoint.

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“CT-guided biopsies are low cost ... and the sensitivity is very, very high,” Dr. Dingemans said. “In good hands, with a good radiologist, you have a high chance that you will have a good diagnosis of the nodules.” She also noted that a bronchus sign does not impact efficacy.

“I’m very into CT-guided biopsies,” Dr. Dingemans continued, noting that the radiologist at her treatment center takes biopsies with a 10-gauge large-core needle. With this technique, Dr. Dingemans reported a 5.7% pneumothorax rate, which is comparable with the present NAVIGATE data.

However, Dr. Lau contested this figure.

“The pneumothorax rates [for CT-guided biopsy] in larger studies have always been about 20% to 40%,” Dr. Lau said. “You can’t compare large overall practice in a pragmatic study capturing everyone versus one single center. The truth is, most centers will have a 20% pneumothorax rate.”

Dr. Lau added that patient experiences are likely to be better with ENB than with CT-guided percutaneous biopsy.

“To me, patient comfort for biopsy is essential,” Dr. Lau said. “Having a needle stuck into your chest – it’s very uncomfortable. I’ve had patients who’ve come to me after they had a percutaneous biopsy and who for some reason needed a re-biopsy ... those patients almost always wish they had navigational bronchoscopy the first time because there would be no pain for them.”

When asked about capital cost concerns surrounding ENB, Dr. Lau suggested that the benefits outweigh the costs.

“The most expensive procedure is the one you have to do again,” Dr. Lau said. “So what we do is put a brush in, and a needle, and a biopsy, and hopefully, one of those three, if not all three, gets tissue, and we can do that with navigational bronchoscopy because there is one channel down. You can’t repeatedly stick needles into patients. By definition, you can’t throw three needle jabs, because you will get a 90% pneumothorax rate. And that’s the beauty of navigational bronchoscopy as well, because in the NAVIGATE series, a number of patients, about 10%, had multiple lesions biopsied.” Furthermore, Dr. Lau noted, percutaneous biopsy is “almost never” performed bilaterally, for fear of collapsing both lungs, but this is not the case with ENB. “We’ve done it on patients who have one lung,” he said.

Dr. Lau predicted that costs of ENB will come down with time. “Because of the number of products increasing, the price will drop,” he said.

Concluding the interview, Dr. Lau offered a summarizing message: “If you want to give the patient the safe option, you should do [ENB], and when it becomes more popular, the price will fall,” he said.

Medtronic funded the study. The investigators reported financial relationships with Olympus, Ambu, PulmonX, Boston Scientific, and others.

SOURCE: Lau et al. ELCC 2019. Abstract 68O.