Photodynamic therapy (PDT) using daylight was as effective as PDT with an artificial light source in clearing grade I actinic keratoses (AKs) of the face and scalp after 3 months, but was associated with less pain and less severe side effects in a small Italian study.

In addition, most of the patients preferred the treatment with daylight photodynamic therapy (DL-PDT), reported Dr. Maria Concetta Fargnoli of the University of L’Aquila (Italy) and her associates (J Eur Acad Dermatol Venereol. 2015 Oct;29[10]:1926-32).

The prospective intrapatient study compared the effects of DL-PDT with conventional PDT (c-PDT) at 3 months in 35 patients with multiple grade I AKs of the face and scalp in September and October 2013. Patients were treated with c-PDT on one side of the face and DL-PDT on the other side. For c-PDT, light therapy was administered after methyl aminolevulinate (MAL) cream was applied to the treatment area and occluded. For DL-PDT, MAL cream was applied to the treatment area, left uncovered for 30 minutes in the dark; patients then exposed these areas to daylight for 2 hours, between 11 a.m. and 3 p.m., after which the cream was wiped off.

At 3 months, the complete response rate of grade I AKs was 87% for DL-PDT and 91% for c-PDT, which was not a significant difference. It was less effective for grade II and III AKs in the study, though, and at 6 months, the recurrence rate for grade I AKs treated with DL-PDT was higher (17%) than for those treated with c-PDT (12%), with a P value less than .05.

Treatment with DL-PDT was associated with significantly less pain and less severe adverse events, with less erythema, crusting, and pustular eruption 2 days after treatment. In addition, 88% of the patients were more satisfied with DL-PDT, the authors said.

“Our study confirms that DL-PDT using MAL is an effective, safe, and convenient alternative for the treatment of grade I AKs ,” they concluded. “Interestingly, clinical response for AK I was significantly moderated by outdoor temperature, increasing at higher temperatures.”

The authors had no conflicts of interest. Dr. Fargnoli received a research grant from Galderma, Italy, but Galderma played no role in the study, according to the study’s disclosure statement. Galderma manufactures the MAL cream product used in the study.

[email protected]

Photodynamic therapy (PDT) using daylight was as effective as PDT with an artificial light source in clearing grade I actinic keratoses (AKs) of the face and scalp after 3 months, but was associated with less pain and less severe side effects in a small Italian study.

In addition, most of the patients preferred the treatment with daylight photodynamic therapy (DL-PDT), reported Dr. Maria Concetta Fargnoli of the University of L’Aquila (Italy) and her associates (J Eur Acad Dermatol Venereol. 2015 Oct;29[10]:1926-32).

The prospective intrapatient study compared the effects of DL-PDT with conventional PDT (c-PDT) at 3 months in 35 patients with multiple grade I AKs of the face and scalp in September and October 2013. Patients were treated with c-PDT on one side of the face and DL-PDT on the other side. For c-PDT, light therapy was administered after methyl aminolevulinate (MAL) cream was applied to the treatment area and occluded. For DL-PDT, MAL cream was applied to the treatment area, left uncovered for 30 minutes in the dark; patients then exposed these areas to daylight for 2 hours, between 11 a.m. and 3 p.m., after which the cream was wiped off.

At 3 months, the complete response rate of grade I AKs was 87% for DL-PDT and 91% for c-PDT, which was not a significant difference. It was less effective for grade II and III AKs in the study, though, and at 6 months, the recurrence rate for grade I AKs treated with DL-PDT was higher (17%) than for those treated with c-PDT (12%), with a P value less than .05.

Treatment with DL-PDT was associated with significantly less pain and less severe adverse events, with less erythema, crusting, and pustular eruption 2 days after treatment. In addition, 88% of the patients were more satisfied with DL-PDT, the authors said.

“Our study confirms that DL-PDT using MAL is an effective, safe, and convenient alternative for the treatment of grade I AKs ,” they concluded. “Interestingly, clinical response for AK I was significantly moderated by outdoor temperature, increasing at higher temperatures.”

The authors had no conflicts of interest. Dr. Fargnoli received a research grant from Galderma, Italy, but Galderma played no role in the study, according to the study’s disclosure statement. Galderma manufactures the MAL cream product used in the study.

[email protected]

Photodynamic therapy (PDT) using daylight was as effective as PDT with an artificial light source in clearing grade I actinic keratoses (AKs) of the face and scalp after 3 months, but was associated with less pain and less severe side effects in a small Italian study.

In addition, most of the patients preferred the treatment with daylight photodynamic therapy (DL-PDT), reported Dr. Maria Concetta Fargnoli of the University of L’Aquila (Italy) and her associates (J Eur Acad Dermatol Venereol. 2015 Oct;29[10]:1926-32).

The prospective intrapatient study compared the effects of DL-PDT with conventional PDT (c-PDT) at 3 months in 35 patients with multiple grade I AKs of the face and scalp in September and October 2013. Patients were treated with c-PDT on one side of the face and DL-PDT on the other side. For c-PDT, light therapy was administered after methyl aminolevulinate (MAL) cream was applied to the treatment area and occluded. For DL-PDT, MAL cream was applied to the treatment area, left uncovered for 30 minutes in the dark; patients then exposed these areas to daylight for 2 hours, between 11 a.m. and 3 p.m., after which the cream was wiped off.

At 3 months, the complete response rate of grade I AKs was 87% for DL-PDT and 91% for c-PDT, which was not a significant difference. It was less effective for grade II and III AKs in the study, though, and at 6 months, the recurrence rate for grade I AKs treated with DL-PDT was higher (17%) than for those treated with c-PDT (12%), with a P value less than .05.

Treatment with DL-PDT was associated with significantly less pain and less severe adverse events, with less erythema, crusting, and pustular eruption 2 days after treatment. In addition, 88% of the patients were more satisfied with DL-PDT, the authors said.

“Our study confirms that DL-PDT using MAL is an effective, safe, and convenient alternative for the treatment of grade I AKs ,” they concluded. “Interestingly, clinical response for AK I was significantly moderated by outdoor temperature, increasing at higher temperatures.”

The authors had no conflicts of interest. Dr. Fargnoli received a research grant from Galderma, Italy, but Galderma played no role in the study, according to the study’s disclosure statement. Galderma manufactures the MAL cream product used in the study.

[email protected]

Over the past 2 decades, more and more people have been treated with antidepressant medications. In the same period of time, suicide rates have gone up – not down. To those of us who treat patients, this fact is both surprising and perplexing. It seems that suicidal thoughts are a common feature of major depression, and when the depressive symptoms abate with treatment, the suicidal thoughts dissipate. Intuitively, it seems that treating depression on a larger scale should prevent suicides, but we still don’t know that conclusively.

According to the National Health and Nutrition Examination Survey (NHANES), 11% percent of Americans over the age of 12 are taking an antidepressant medication. In women aged 40-59, this number is 23%. Of those taking antidepressants, only one-third have seen a mental health professional in the past 12 months. What also is striking is that for people surveyed with symptoms of severe depression, only one-third were on medication.

In 2013, just over 40,000 Americans died of suicide. From 2000 to 2013, the suicide rate per 100,000 Americans has steadily increased from 10.4 to 12.6 per 100,000 people. While we know that people with psychiatric illnesses have higher rates of suicide compared with the general population, what we don’t know is whether the people dying are the same people who are getting treatment.

Thinking about this gets very difficult. It has been estimated that 90% of those who die of suicide have suffered from a mental illness. This figure includes those who were treated, untreated, and previously treated, but the studies have methodologic inconsistencies and that 90% estimate may not be accurate. Certainly, however, people die of suicide for reasons that have nothing to do with psychiatric illness, and we do know that impulsive responses to distressing circumstances are a factor, especially when a lethal method is easily available.

Several studies have shown that antidepressant use, particularly in older adults, may be associated with a decrease in suicidality. The studies often combine suicide attempts and completions. The issues with younger patients are more complicated, and in recent weeks, the reanalysis of the 2001 Paxil 329 study has again raised issues about the safety of certain antidepressants in children and adolescents. The data for all these studies are both confusing and contradictory, and are not easy to examine or interpret.

We also don’t know what role psychotherapy plays. A study done at Johns Hopkins Bloomberg School of Public Health looked at the follow-up for 65,000 people in Denmark who had attempted suicide and found that the rates for completed suicide dropped if the patient received a short course of psychosocial therapy at a suicide prevention center. But again, this study looked at a select group of people who had already attempted suicide.

I began to think it might help to ask these questions in a closed system where patients could be tallied with regard to requests for treatment, what type of treatment was provided, and even access to autopsy results. The U.S. Department of Veterans Affairs seemed to be a source where such answers might be found. It has been reported that 22 veterans a day die by suicide, and many veterans get their care in VA facilities, with VA pharmacy benefits, and treatment effects can, in theory, be studied.

Hoping to get a better sense of the relationship between treatment and suicide, I met with Robert Bossarte, Ph.D., director of the Epidemiology Program in the VA’s Office of Public Health. His career has been focused on suicide prevention.

The first thing Dr. Bossarte did was dissuade me of the idea that the VA is a closed system. Not all veterans receive lifelong benefits from the VA, and the formulas for determining who is entitled to what benefits, and for how long, is rather complicated. Dr. Bossarte also noted that some patients go outside of the system for their care.

“What we do know is that among those who have used VA services in the previous year, about 2,000 veterans a year die from suicide. It’s been hovering around that for the past decade,” Dr. Bossarte explained, again emphasizing that many veterans do not receive care at VA facilities. “We published a report in 2012 where we estimated 22 veterans a day die by suicide and that caught fire, but it is purely an estimate. The truth is we have no idea what the real count is, because until we began working on the Suicide Data Repository there was no national register of veteran mortality and there has been no way for us to know.”

Dr. Bossarte anticipates that the VA will have the data necessary to calculate more accurate statistics by the end of the year. “More than 70% of veteran suicide are in people over age 50; but the rates are going up most among the youngest.”

A notable drop in veteran suicide rates for those who used services occurred between 2001 and 2003, and that decrease remains unexplained; it preceded later changes in mental health services and enhanced suicide prevention programs. Dr. Bossarte also pointed out that just under half of veterans who die from suicide have no mental health diagnosis, despite yearly screening to identify people who may be suffering from posttraumatic stress disorder, alcohol-related disorders, and depression.

“The attention on veteran suicide started around 2007,” Dr. Bossarte explained. “Mark Kaplan published a study using publicly available mortality data; those who reported they were veterans were twice as likely to die of suicide as those who were not.”

While this sparked interest in veteran suicide, it’s important to note that a replication of that study in 2012 by Matthew Miller did not have the same findings.

“Then, in 2008, for the first time in recent history,” Dr. Bossarte continued, “the suicide rate among active duty military personnel exceeded that of the general population. Traditionally, rates of suicide in this population have been 40%-50% lower than in the general population. The increased rate was seen primarily in the Army and Marines. Serious mental illness may make people ineligible for military service, as can violent and disruptive behavior – things that are associated with suicide – so you tended to get a healthier population in the military.”

Dr. Bossarte noted that there was conjecture that increased suicide rates among active military might be related to more waivers that allowed people to enlist who would not ordinarily be eligible, and/or to higher rates of deployment. He went on to talk about Army STARRS (Army Study to Assess Risk and Resilience in Servicemembers).

“STARRS devoted $50 million over 5 years to the largest suicide study and did not find an effect of waivers. They did report a higher suicide rate among those who were deployed, however. But then Tim Bullman in my office looked at suicide rates 7 years after separation from service, and he reported a higher suicide rate among those who were never deployed.” The VA studies, I quickly realized, were also confusing and contradictory.

The VA has greatly expanded its mental health and suicide prevention services. For veterans overall, suicide rates have stabilized, but they have not decreased. For those veterans with psychiatric disorders, however, the suicide rates have gone down.

“When you ask ‘does treatment matter?’ it’s so hard to disentangle psychotherapy from pharmacotherapy. Over the past decade, we’ve seen a significant decrease in the suicide rate among those veterans with mental health disorders. We’ve looked at suicide rates every way you can think of. One thing we do know is that the better the relationship with the clinician, the lower the suicide risk.”

We talked about the role of hospitalization in preventing suicide, and Dr. Bossarte noted that the highest risk for suicide is immediately following hospital discharge.

“We are looking at people hospitalized after their first-ever suicide attempts and rates of mortality, including suicidal behavior, for 1 year after discharge. In very preliminary findings, we didn’t see any difference in the outcome for either all-cause mortality or repeat suicide attempts in those who were hospitalized, compared to those who were not. We don’t yet know about completed suicide.”

I left my discussion with Dr. Bossarte with more questions than answers. We have reason to believe that treatment helps, but we still don’t know which treatments help which people, and we do know that treatment doesn’t prevent suicide in every patient. In a culture where “treatment” has come to be equated with “prescribing” and is often based on a checklist of symptoms done by a primary care clinician, one might wonder if combining psychotherapy and medication – an increasingly rare offering – might have a better outcome. Simply put, for a problem that prematurely takes more than 40,000 lives a year, we know much too little.

Dr. Miller is a coauthor of “Shrink Rap: Three Psychiatrists Explain Their Work” (Baltimore: Johns Hopkins University Press, 2011).

Over the past 2 decades, more and more people have been treated with antidepressant medications. In the same period of time, suicide rates have gone up – not down. To those of us who treat patients, this fact is both surprising and perplexing. It seems that suicidal thoughts are a common feature of major depression, and when the depressive symptoms abate with treatment, the suicidal thoughts dissipate. Intuitively, it seems that treating depression on a larger scale should prevent suicides, but we still don’t know that conclusively.

According to the National Health and Nutrition Examination Survey (NHANES), 11% percent of Americans over the age of 12 are taking an antidepressant medication. In women aged 40-59, this number is 23%. Of those taking antidepressants, only one-third have seen a mental health professional in the past 12 months. What also is striking is that for people surveyed with symptoms of severe depression, only one-third were on medication.

In 2013, just over 40,000 Americans died of suicide. From 2000 to 2013, the suicide rate per 100,000 Americans has steadily increased from 10.4 to 12.6 per 100,000 people. While we know that people with psychiatric illnesses have higher rates of suicide compared with the general population, what we don’t know is whether the people dying are the same people who are getting treatment.

Thinking about this gets very difficult. It has been estimated that 90% of those who die of suicide have suffered from a mental illness. This figure includes those who were treated, untreated, and previously treated, but the studies have methodologic inconsistencies and that 90% estimate may not be accurate. Certainly, however, people die of suicide for reasons that have nothing to do with psychiatric illness, and we do know that impulsive responses to distressing circumstances are a factor, especially when a lethal method is easily available.

Several studies have shown that antidepressant use, particularly in older adults, may be associated with a decrease in suicidality. The studies often combine suicide attempts and completions. The issues with younger patients are more complicated, and in recent weeks, the reanalysis of the 2001 Paxil 329 study has again raised issues about the safety of certain antidepressants in children and adolescents. The data for all these studies are both confusing and contradictory, and are not easy to examine or interpret.

We also don’t know what role psychotherapy plays. A study done at Johns Hopkins Bloomberg School of Public Health looked at the follow-up for 65,000 people in Denmark who had attempted suicide and found that the rates for completed suicide dropped if the patient received a short course of psychosocial therapy at a suicide prevention center. But again, this study looked at a select group of people who had already attempted suicide.

I began to think it might help to ask these questions in a closed system where patients could be tallied with regard to requests for treatment, what type of treatment was provided, and even access to autopsy results. The U.S. Department of Veterans Affairs seemed to be a source where such answers might be found. It has been reported that 22 veterans a day die by suicide, and many veterans get their care in VA facilities, with VA pharmacy benefits, and treatment effects can, in theory, be studied.

Hoping to get a better sense of the relationship between treatment and suicide, I met with Robert Bossarte, Ph.D., director of the Epidemiology Program in the VA’s Office of Public Health. His career has been focused on suicide prevention.

The first thing Dr. Bossarte did was dissuade me of the idea that the VA is a closed system. Not all veterans receive lifelong benefits from the VA, and the formulas for determining who is entitled to what benefits, and for how long, is rather complicated. Dr. Bossarte also noted that some patients go outside of the system for their care.

“What we do know is that among those who have used VA services in the previous year, about 2,000 veterans a year die from suicide. It’s been hovering around that for the past decade,” Dr. Bossarte explained, again emphasizing that many veterans do not receive care at VA facilities. “We published a report in 2012 where we estimated 22 veterans a day die by suicide and that caught fire, but it is purely an estimate. The truth is we have no idea what the real count is, because until we began working on the Suicide Data Repository there was no national register of veteran mortality and there has been no way for us to know.”

Dr. Bossarte anticipates that the VA will have the data necessary to calculate more accurate statistics by the end of the year. “More than 70% of veteran suicide are in people over age 50; but the rates are going up most among the youngest.”

A notable drop in veteran suicide rates for those who used services occurred between 2001 and 2003, and that decrease remains unexplained; it preceded later changes in mental health services and enhanced suicide prevention programs. Dr. Bossarte also pointed out that just under half of veterans who die from suicide have no mental health diagnosis, despite yearly screening to identify people who may be suffering from posttraumatic stress disorder, alcohol-related disorders, and depression.

“The attention on veteran suicide started around 2007,” Dr. Bossarte explained. “Mark Kaplan published a study using publicly available mortality data; those who reported they were veterans were twice as likely to die of suicide as those who were not.”

While this sparked interest in veteran suicide, it’s important to note that a replication of that study in 2012 by Matthew Miller did not have the same findings.

“Then, in 2008, for the first time in recent history,” Dr. Bossarte continued, “the suicide rate among active duty military personnel exceeded that of the general population. Traditionally, rates of suicide in this population have been 40%-50% lower than in the general population. The increased rate was seen primarily in the Army and Marines. Serious mental illness may make people ineligible for military service, as can violent and disruptive behavior – things that are associated with suicide – so you tended to get a healthier population in the military.”

Dr. Bossarte noted that there was conjecture that increased suicide rates among active military might be related to more waivers that allowed people to enlist who would not ordinarily be eligible, and/or to higher rates of deployment. He went on to talk about Army STARRS (Army Study to Assess Risk and Resilience in Servicemembers).

“STARRS devoted $50 million over 5 years to the largest suicide study and did not find an effect of waivers. They did report a higher suicide rate among those who were deployed, however. But then Tim Bullman in my office looked at suicide rates 7 years after separation from service, and he reported a higher suicide rate among those who were never deployed.” The VA studies, I quickly realized, were also confusing and contradictory.

The VA has greatly expanded its mental health and suicide prevention services. For veterans overall, suicide rates have stabilized, but they have not decreased. For those veterans with psychiatric disorders, however, the suicide rates have gone down.

“When you ask ‘does treatment matter?’ it’s so hard to disentangle psychotherapy from pharmacotherapy. Over the past decade, we’ve seen a significant decrease in the suicide rate among those veterans with mental health disorders. We’ve looked at suicide rates every way you can think of. One thing we do know is that the better the relationship with the clinician, the lower the suicide risk.”

We talked about the role of hospitalization in preventing suicide, and Dr. Bossarte noted that the highest risk for suicide is immediately following hospital discharge.

“We are looking at people hospitalized after their first-ever suicide attempts and rates of mortality, including suicidal behavior, for 1 year after discharge. In very preliminary findings, we didn’t see any difference in the outcome for either all-cause mortality or repeat suicide attempts in those who were hospitalized, compared to those who were not. We don’t yet know about completed suicide.”

I left my discussion with Dr. Bossarte with more questions than answers. We have reason to believe that treatment helps, but we still don’t know which treatments help which people, and we do know that treatment doesn’t prevent suicide in every patient. In a culture where “treatment” has come to be equated with “prescribing” and is often based on a checklist of symptoms done by a primary care clinician, one might wonder if combining psychotherapy and medication – an increasingly rare offering – might have a better outcome. Simply put, for a problem that prematurely takes more than 40,000 lives a year, we know much too little.

Dr. Miller is a coauthor of “Shrink Rap: Three Psychiatrists Explain Their Work” (Baltimore: Johns Hopkins University Press, 2011).

Over the past 2 decades, more and more people have been treated with antidepressant medications. In the same period of time, suicide rates have gone up – not down. To those of us who treat patients, this fact is both surprising and perplexing. It seems that suicidal thoughts are a common feature of major depression, and when the depressive symptoms abate with treatment, the suicidal thoughts dissipate. Intuitively, it seems that treating depression on a larger scale should prevent suicides, but we still don’t know that conclusively.

According to the National Health and Nutrition Examination Survey (NHANES), 11% percent of Americans over the age of 12 are taking an antidepressant medication. In women aged 40-59, this number is 23%. Of those taking antidepressants, only one-third have seen a mental health professional in the past 12 months. What also is striking is that for people surveyed with symptoms of severe depression, only one-third were on medication.

In 2013, just over 40,000 Americans died of suicide. From 2000 to 2013, the suicide rate per 100,000 Americans has steadily increased from 10.4 to 12.6 per 100,000 people. While we know that people with psychiatric illnesses have higher rates of suicide compared with the general population, what we don’t know is whether the people dying are the same people who are getting treatment.

Thinking about this gets very difficult. It has been estimated that 90% of those who die of suicide have suffered from a mental illness. This figure includes those who were treated, untreated, and previously treated, but the studies have methodologic inconsistencies and that 90% estimate may not be accurate. Certainly, however, people die of suicide for reasons that have nothing to do with psychiatric illness, and we do know that impulsive responses to distressing circumstances are a factor, especially when a lethal method is easily available.

Several studies have shown that antidepressant use, particularly in older adults, may be associated with a decrease in suicidality. The studies often combine suicide attempts and completions. The issues with younger patients are more complicated, and in recent weeks, the reanalysis of the 2001 Paxil 329 study has again raised issues about the safety of certain antidepressants in children and adolescents. The data for all these studies are both confusing and contradictory, and are not easy to examine or interpret.

We also don’t know what role psychotherapy plays. A study done at Johns Hopkins Bloomberg School of Public Health looked at the follow-up for 65,000 people in Denmark who had attempted suicide and found that the rates for completed suicide dropped if the patient received a short course of psychosocial therapy at a suicide prevention center. But again, this study looked at a select group of people who had already attempted suicide.

I began to think it might help to ask these questions in a closed system where patients could be tallied with regard to requests for treatment, what type of treatment was provided, and even access to autopsy results. The U.S. Department of Veterans Affairs seemed to be a source where such answers might be found. It has been reported that 22 veterans a day die by suicide, and many veterans get their care in VA facilities, with VA pharmacy benefits, and treatment effects can, in theory, be studied.

Hoping to get a better sense of the relationship between treatment and suicide, I met with Robert Bossarte, Ph.D., director of the Epidemiology Program in the VA’s Office of Public Health. His career has been focused on suicide prevention.

The first thing Dr. Bossarte did was dissuade me of the idea that the VA is a closed system. Not all veterans receive lifelong benefits from the VA, and the formulas for determining who is entitled to what benefits, and for how long, is rather complicated. Dr. Bossarte also noted that some patients go outside of the system for their care.

“What we do know is that among those who have used VA services in the previous year, about 2,000 veterans a year die from suicide. It’s been hovering around that for the past decade,” Dr. Bossarte explained, again emphasizing that many veterans do not receive care at VA facilities. “We published a report in 2012 where we estimated 22 veterans a day die by suicide and that caught fire, but it is purely an estimate. The truth is we have no idea what the real count is, because until we began working on the Suicide Data Repository there was no national register of veteran mortality and there has been no way for us to know.”

Dr. Bossarte anticipates that the VA will have the data necessary to calculate more accurate statistics by the end of the year. “More than 70% of veteran suicide are in people over age 50; but the rates are going up most among the youngest.”

A notable drop in veteran suicide rates for those who used services occurred between 2001 and 2003, and that decrease remains unexplained; it preceded later changes in mental health services and enhanced suicide prevention programs. Dr. Bossarte also pointed out that just under half of veterans who die from suicide have no mental health diagnosis, despite yearly screening to identify people who may be suffering from posttraumatic stress disorder, alcohol-related disorders, and depression.

“The attention on veteran suicide started around 2007,” Dr. Bossarte explained. “Mark Kaplan published a study using publicly available mortality data; those who reported they were veterans were twice as likely to die of suicide as those who were not.”

While this sparked interest in veteran suicide, it’s important to note that a replication of that study in 2012 by Matthew Miller did not have the same findings.

“Then, in 2008, for the first time in recent history,” Dr. Bossarte continued, “the suicide rate among active duty military personnel exceeded that of the general population. Traditionally, rates of suicide in this population have been 40%-50% lower than in the general population. The increased rate was seen primarily in the Army and Marines. Serious mental illness may make people ineligible for military service, as can violent and disruptive behavior – things that are associated with suicide – so you tended to get a healthier population in the military.”

Dr. Bossarte noted that there was conjecture that increased suicide rates among active military might be related to more waivers that allowed people to enlist who would not ordinarily be eligible, and/or to higher rates of deployment. He went on to talk about Army STARRS (Army Study to Assess Risk and Resilience in Servicemembers).

“STARRS devoted $50 million over 5 years to the largest suicide study and did not find an effect of waivers. They did report a higher suicide rate among those who were deployed, however. But then Tim Bullman in my office looked at suicide rates 7 years after separation from service, and he reported a higher suicide rate among those who were never deployed.” The VA studies, I quickly realized, were also confusing and contradictory.

The VA has greatly expanded its mental health and suicide prevention services. For veterans overall, suicide rates have stabilized, but they have not decreased. For those veterans with psychiatric disorders, however, the suicide rates have gone down.

“When you ask ‘does treatment matter?’ it’s so hard to disentangle psychotherapy from pharmacotherapy. Over the past decade, we’ve seen a significant decrease in the suicide rate among those veterans with mental health disorders. We’ve looked at suicide rates every way you can think of. One thing we do know is that the better the relationship with the clinician, the lower the suicide risk.”

We talked about the role of hospitalization in preventing suicide, and Dr. Bossarte noted that the highest risk for suicide is immediately following hospital discharge.

“We are looking at people hospitalized after their first-ever suicide attempts and rates of mortality, including suicidal behavior, for 1 year after discharge. In very preliminary findings, we didn’t see any difference in the outcome for either all-cause mortality or repeat suicide attempts in those who were hospitalized, compared to those who were not. We don’t yet know about completed suicide.”

I left my discussion with Dr. Bossarte with more questions than answers. We have reason to believe that treatment helps, but we still don’t know which treatments help which people, and we do know that treatment doesn’t prevent suicide in every patient. In a culture where “treatment” has come to be equated with “prescribing” and is often based on a checklist of symptoms done by a primary care clinician, one might wonder if combining psychotherapy and medication – an increasingly rare offering – might have a better outcome. Simply put, for a problem that prematurely takes more than 40,000 lives a year, we know much too little.

Dr. Miller is a coauthor of “Shrink Rap: Three Psychiatrists Explain Their Work” (Baltimore: Johns Hopkins University Press, 2011).

Recurrent venous thromboembolism was significantly associated with a higher European Society of Cardiology (ESC) pulmonary embolism score. This association was independent of other factors such as age, sex, and body mass index, according to a long-term, prospective follow-up study of 627 patients with a first episode of pulmonary embolism.

In addition, unprovoked PE and varicose veins of the lower limbs also increased recurrence risk, while longer anticoagulation treatment reduced it (Intnl J Cardiol. 2016;202:275-81).

Courtesy Dr. James Heilman

Dr. Shuai Zhang of the Beijing Institute of Respiratory Medicine and coauthors categorized their patients into three groups according to the ESC risk stratification model (Eur Heart J. 2008;29:2276-315). These were low-, intermediate-, and high-risk groups. Of the 627 patients, 84 had suspected VTE recurrence, 68 of whom had this confirmed by imaging diagnosis and were designated as the recurrent group. The 1-, 2-, and 5-year cumulative incidences of recurrent VTE were 4.5%. 7.3%, and 13.9%, respectively.

The researchers compared the 68 recurrent to the 559 nonrecurrent patients; all patients had had a first episode of PE.

Compared with nonrecurrent VTE patients, the recurrent group had significantly more high-risk and intermediate-risk patients, and the high-risk and intermediate-risk patients overall had significantly more cumulative recurrent events than the low-risk group. Multivariate analysis confirmed the association between higher risk in ESC stratification and VTE recurrence independent of age, sex, and body mass index.

Based on these results, the authors stated that, “The severity of disease should be considered in determining the initial treatment and duration of follow-up anticoagulation.”

“These finding support the notion that optimized therapy based on risk stratification is valuable while treating PE patients,” they concluded.

The authors reported having no conflicts of interest.

Read the full study online in the International Journal of Cardiology.

[email protected]

Recurrent venous thromboembolism was significantly associated with a higher European Society of Cardiology (ESC) pulmonary embolism score. This association was independent of other factors such as age, sex, and body mass index, according to a long-term, prospective follow-up study of 627 patients with a first episode of pulmonary embolism.

In addition, unprovoked PE and varicose veins of the lower limbs also increased recurrence risk, while longer anticoagulation treatment reduced it (Intnl J Cardiol. 2016;202:275-81).

Courtesy Dr. James Heilman

Dr. Shuai Zhang of the Beijing Institute of Respiratory Medicine and coauthors categorized their patients into three groups according to the ESC risk stratification model (Eur Heart J. 2008;29:2276-315). These were low-, intermediate-, and high-risk groups. Of the 627 patients, 84 had suspected VTE recurrence, 68 of whom had this confirmed by imaging diagnosis and were designated as the recurrent group. The 1-, 2-, and 5-year cumulative incidences of recurrent VTE were 4.5%. 7.3%, and 13.9%, respectively.

The researchers compared the 68 recurrent to the 559 nonrecurrent patients; all patients had had a first episode of PE.

Compared with nonrecurrent VTE patients, the recurrent group had significantly more high-risk and intermediate-risk patients, and the high-risk and intermediate-risk patients overall had significantly more cumulative recurrent events than the low-risk group. Multivariate analysis confirmed the association between higher risk in ESC stratification and VTE recurrence independent of age, sex, and body mass index.

Based on these results, the authors stated that, “The severity of disease should be considered in determining the initial treatment and duration of follow-up anticoagulation.”

“These finding support the notion that optimized therapy based on risk stratification is valuable while treating PE patients,” they concluded.

The authors reported having no conflicts of interest.

Read the full study online in the International Journal of Cardiology.

[email protected]

Recurrent venous thromboembolism was significantly associated with a higher European Society of Cardiology (ESC) pulmonary embolism score. This association was independent of other factors such as age, sex, and body mass index, according to a long-term, prospective follow-up study of 627 patients with a first episode of pulmonary embolism.

In addition, unprovoked PE and varicose veins of the lower limbs also increased recurrence risk, while longer anticoagulation treatment reduced it (Intnl J Cardiol. 2016;202:275-81).

Courtesy Dr. James Heilman

Dr. Shuai Zhang of the Beijing Institute of Respiratory Medicine and coauthors categorized their patients into three groups according to the ESC risk stratification model (Eur Heart J. 2008;29:2276-315). These were low-, intermediate-, and high-risk groups. Of the 627 patients, 84 had suspected VTE recurrence, 68 of whom had this confirmed by imaging diagnosis and were designated as the recurrent group. The 1-, 2-, and 5-year cumulative incidences of recurrent VTE were 4.5%. 7.3%, and 13.9%, respectively.

The researchers compared the 68 recurrent to the 559 nonrecurrent patients; all patients had had a first episode of PE.

Compared with nonrecurrent VTE patients, the recurrent group had significantly more high-risk and intermediate-risk patients, and the high-risk and intermediate-risk patients overall had significantly more cumulative recurrent events than the low-risk group. Multivariate analysis confirmed the association between higher risk in ESC stratification and VTE recurrence independent of age, sex, and body mass index.

Based on these results, the authors stated that, “The severity of disease should be considered in determining the initial treatment and duration of follow-up anticoagulation.”

“These finding support the notion that optimized therapy based on risk stratification is valuable while treating PE patients,” they concluded.

The authors reported having no conflicts of interest.

Read the full study online in the International Journal of Cardiology.

[email protected]

To the Editor:

Staphylococcal scalded skin syndrome (SSSS) is a superficial blistering disorder mediated by Staphylococcus aureus exfoliative toxins (ETs).¹ It is rare in adults, but when diagnosed, it is often associated with renal failure, immunodeficiency, or overwhelming staphylococcal infection.² We present a unique case of a pregnant woman with chronic atopic dermatitis (AD) who developed SSSS.

A 21-year-old gravida 3, para 2, aborta 0pregnant woman (29 weeks’ gestation) with a history of chronic AD who was hospitalized with facial edema, purulent ocular discharge, and substantial worsening of AD presented for a dermatology consultation. Her AD was previously managed with topical steroids but had been complicated by multiple methicillin-resistant Staphylococcus aureus (MRSA) infections. On physical examination, she had substantial periorbital edema with purulent discharge from both eyes (Figure 1A), perioral crust with radial fissures (Figure 2A), and mild generalized facial swelling and desquamation (Figure 3). However, the oral cavity was not involved. She had diffuse desquamation in addition to chronic lichenified plaques of the arms, legs, and trunk and SSSS was clinically diagnosed. Cultures of conjunctival discharge were positive for MRSA. The patient was treated with intravenous vancomycin and had a full recovery (Figures 1B and 2B). She delivered a healthy newborn with Apgar scores of 9 and 9 at 1 and 5 minutes, respectively, at 36 weeks and 6 days’ gestation by cesarean delivery; however, her postoperative care was complicated by preeclampsia, which was treated with magnesium sulfate. The newborn showed no evidence of infection or blistering at birth or during the hospital stay.

Figure 1. Periorbital edema with purulent ocular discharge before (A) and after (B) treatment.			Figure 2. Perioral desquamation and radial fissuring before (A) and after (B) treatment.

Staphylococcal scalded skin syndrome is a superficial blistering disorder that ranges in severity from localized blisters to generalized exfoliation.¹ Exfoliative toxin is the major virulence factor responsible for SSSS. Exfoliative toxin is a serine protease that targets desmoglein 1, resulting in intraepidermal separation of keratinocytes.³ Two serologically distinct exfoliative toxins—ETA and ETB—have been associated with human disease.⁴ Although ETA is encoded on a phage genome, ETB is encoded on a large plasmid.³ Initially it was thought that only strains of S aureus carrying lytic group II phages were responsible for ET production; however, it is now accepted that all phage groups are capable of producing ET and causing SSSS.¹

Staphylococcal scalded skin syndrome is most common in infants and children and rare in adults. Although it has been occasionally described in otherwise healthy adults,⁵ it is most often diagnosed in patients with renal failure (decreased toxin excretion), immunodeficiency (lack of antibodies against toxins), and overwhelming staphylococcal infection (excessive toxin).² Mortality in treated children is low, but it can reach almost 60% in adults¹; therefore, defining risk factors that may aid in early diagnosis are exceedingly important.

We believe that both our patient’s history of 
AD and her pregnancy contributed to the development of SSSS. The patient had a history of multiple MRSA infections prior to this hospitalization, suggesting MRSA colonization, which is a common complication of AD with more than 75% of 
AD patients colonized with S aureus.⁶ Additionally, 
S aureus superantigen stimulation can result in the loss of regulatory T cells’ natural immunosuppression. Regulatory T cells are remarkably increased in patients with AD; therefore, the inflammatory response to S aureus is likely amplified in an atopic patient, as there is more native immunosuppressive capacity to be affected.⁴ Furthermore, we believe that pregnancy and its associated immunomodulation is a risk for SSSS. Immune changes in pregnancy are still not well understood; however, it is known that there are alterations to allow symbiosis between the mother and fetus. Anti-ET IgG antibodies are thought to play an important role in protecting against SSSS. Historically, studies on serum immunoglobulin levels during pregnancy have had conflicting findings. They have shown that IgG is either unchanged or decreased, while IgA, IgE, and IgM can be increased, decreased, or unchanged.⁷ In a study of immunoglobulins in pregnancy, Bahna et al⁷ showed that IgE is unchanged over the course of pregnancy, but their analysis did not address IgG levels. If IgG levels in fact decrease during pregnancy, the mother could be at risk for SSSS due to her inability to neutralize toxins. Even if total IgG levels remain unchanged, it is possible that specific antitoxin antibodies are decreased. Additionally, there is a documented suppression and alteration in T-cell response to prevent fetal rejection during pregnancy.⁸ Adult SSSS has been documented several times in human immunodeficiency virus–positive patients, suggesting there may be some association between T-cell suppression and SSSS susceptibility.⁹ Interestingly, pregnancy, similar to AD, results in an increase in immunosuppressive T cells,¹⁰ which, if deactivated by superantigens, could potentially contribute to an increased inflammatory response. All of these immune system alterations likely leave the mother vulnerable to toxin-mediated events such as SSSS.

We believe this case highlights the importance of considering SSSS in both atopic and pregnant patients with desquamating eruptions. In the case of pregnant patients, it is important to consider the risks and benefits of any medical treatments for both the mother and infant. Vancomycin is a pregnancy category B drug and was chosen for its known effectiveness and safety in pregnancy. One study compared 10 babies with mothers who were treated with vancomycin during the second and third trimesters for MRSA to 20 babies with mothers who did not receive vancomycin and did not find an increased risk for sensorineural hearing loss or nephrotoxicity.¹¹ There is no known increased risk for preeclampsia with vancomycin, but some studies have suggested that maternal infection independently increases the risk for preeclampsia.¹² Other treatment options were not as safe as vancomycin in this case: doxycycline is contraindicated (pregnancy category D) due to the potential for staining of deciduous teeth and skeletal growth impairment, trimethoprim-sulfamethoxazole is a pregnancy category D drug during the third trimester due to the risk of kernicterus, and linezolid is a pregnancy category C drug.¹³

To the Editor:

Staphylococcal scalded skin syndrome (SSSS) is a superficial blistering disorder mediated by Staphylococcus aureus exfoliative toxins (ETs).¹ It is rare in adults, but when diagnosed, it is often associated with renal failure, immunodeficiency, or overwhelming staphylococcal infection.² We present a unique case of a pregnant woman with chronic atopic dermatitis (AD) who developed SSSS.

A 21-year-old gravida 3, para 2, aborta 0pregnant woman (29 weeks’ gestation) with a history of chronic AD who was hospitalized with facial edema, purulent ocular discharge, and substantial worsening of AD presented for a dermatology consultation. Her AD was previously managed with topical steroids but had been complicated by multiple methicillin-resistant Staphylococcus aureus (MRSA) infections. On physical examination, she had substantial periorbital edema with purulent discharge from both eyes (Figure 1A), perioral crust with radial fissures (Figure 2A), and mild generalized facial swelling and desquamation (Figure 3). However, the oral cavity was not involved. She had diffuse desquamation in addition to chronic lichenified plaques of the arms, legs, and trunk and SSSS was clinically diagnosed. Cultures of conjunctival discharge were positive for MRSA. The patient was treated with intravenous vancomycin and had a full recovery (Figures 1B and 2B). She delivered a healthy newborn with Apgar scores of 9 and 9 at 1 and 5 minutes, respectively, at 36 weeks and 6 days’ gestation by cesarean delivery; however, her postoperative care was complicated by preeclampsia, which was treated with magnesium sulfate. The newborn showed no evidence of infection or blistering at birth or during the hospital stay.

Figure 1. Periorbital edema with purulent ocular discharge before (A) and after (B) treatment.			Figure 2. Perioral desquamation and radial fissuring before (A) and after (B) treatment.

Staphylococcal scalded skin syndrome is a superficial blistering disorder that ranges in severity from localized blisters to generalized exfoliation.¹ Exfoliative toxin is the major virulence factor responsible for SSSS. Exfoliative toxin is a serine protease that targets desmoglein 1, resulting in intraepidermal separation of keratinocytes.³ Two serologically distinct exfoliative toxins—ETA and ETB—have been associated with human disease.⁴ Although ETA is encoded on a phage genome, ETB is encoded on a large plasmid.³ Initially it was thought that only strains of S aureus carrying lytic group II phages were responsible for ET production; however, it is now accepted that all phage groups are capable of producing ET and causing SSSS.¹

Staphylococcal scalded skin syndrome is most common in infants and children and rare in adults. Although it has been occasionally described in otherwise healthy adults,⁵ it is most often diagnosed in patients with renal failure (decreased toxin excretion), immunodeficiency (lack of antibodies against toxins), and overwhelming staphylococcal infection (excessive toxin).² Mortality in treated children is low, but it can reach almost 60% in adults¹; therefore, defining risk factors that may aid in early diagnosis are exceedingly important.

We believe that both our patient’s history of 
AD and her pregnancy contributed to the development of SSSS. The patient had a history of multiple MRSA infections prior to this hospitalization, suggesting MRSA colonization, which is a common complication of AD with more than 75% of 
AD patients colonized with S aureus.⁶ Additionally, 
S aureus superantigen stimulation can result in the loss of regulatory T cells’ natural immunosuppression. Regulatory T cells are remarkably increased in patients with AD; therefore, the inflammatory response to S aureus is likely amplified in an atopic patient, as there is more native immunosuppressive capacity to be affected.⁴ Furthermore, we believe that pregnancy and its associated immunomodulation is a risk for SSSS. Immune changes in pregnancy are still not well understood; however, it is known that there are alterations to allow symbiosis between the mother and fetus. Anti-ET IgG antibodies are thought to play an important role in protecting against SSSS. Historically, studies on serum immunoglobulin levels during pregnancy have had conflicting findings. They have shown that IgG is either unchanged or decreased, while IgA, IgE, and IgM can be increased, decreased, or unchanged.⁷ In a study of immunoglobulins in pregnancy, Bahna et al⁷ showed that IgE is unchanged over the course of pregnancy, but their analysis did not address IgG levels. If IgG levels in fact decrease during pregnancy, the mother could be at risk for SSSS due to her inability to neutralize toxins. Even if total IgG levels remain unchanged, it is possible that specific antitoxin antibodies are decreased. Additionally, there is a documented suppression and alteration in T-cell response to prevent fetal rejection during pregnancy.⁸ Adult SSSS has been documented several times in human immunodeficiency virus–positive patients, suggesting there may be some association between T-cell suppression and SSSS susceptibility.⁹ Interestingly, pregnancy, similar to AD, results in an increase in immunosuppressive T cells,¹⁰ which, if deactivated by superantigens, could potentially contribute to an increased inflammatory response. All of these immune system alterations likely leave the mother vulnerable to toxin-mediated events such as SSSS.

We believe this case highlights the importance of considering SSSS in both atopic and pregnant patients with desquamating eruptions. In the case of pregnant patients, it is important to consider the risks and benefits of any medical treatments for both the mother and infant. Vancomycin is a pregnancy category B drug and was chosen for its known effectiveness and safety in pregnancy. One study compared 10 babies with mothers who were treated with vancomycin during the second and third trimesters for MRSA to 20 babies with mothers who did not receive vancomycin and did not find an increased risk for sensorineural hearing loss or nephrotoxicity.¹¹ There is no known increased risk for preeclampsia with vancomycin, but some studies have suggested that maternal infection independently increases the risk for preeclampsia.¹² Other treatment options were not as safe as vancomycin in this case: doxycycline is contraindicated (pregnancy category D) due to the potential for staining of deciduous teeth and skeletal growth impairment, trimethoprim-sulfamethoxazole is a pregnancy category D drug during the third trimester due to the risk of kernicterus, and linezolid is a pregnancy category C drug.¹³

To the Editor:

Staphylococcal scalded skin syndrome (SSSS) is a superficial blistering disorder mediated by Staphylococcus aureus exfoliative toxins (ETs).¹ It is rare in adults, but when diagnosed, it is often associated with renal failure, immunodeficiency, or overwhelming staphylococcal infection.² We present a unique case of a pregnant woman with chronic atopic dermatitis (AD) who developed SSSS.

A 21-year-old gravida 3, para 2, aborta 0pregnant woman (29 weeks’ gestation) with a history of chronic AD who was hospitalized with facial edema, purulent ocular discharge, and substantial worsening of AD presented for a dermatology consultation. Her AD was previously managed with topical steroids but had been complicated by multiple methicillin-resistant Staphylococcus aureus (MRSA) infections. On physical examination, she had substantial periorbital edema with purulent discharge from both eyes (Figure 1A), perioral crust with radial fissures (Figure 2A), and mild generalized facial swelling and desquamation (Figure 3). However, the oral cavity was not involved. She had diffuse desquamation in addition to chronic lichenified plaques of the arms, legs, and trunk and SSSS was clinically diagnosed. Cultures of conjunctival discharge were positive for MRSA. The patient was treated with intravenous vancomycin and had a full recovery (Figures 1B and 2B). She delivered a healthy newborn with Apgar scores of 9 and 9 at 1 and 5 minutes, respectively, at 36 weeks and 6 days’ gestation by cesarean delivery; however, her postoperative care was complicated by preeclampsia, which was treated with magnesium sulfate. The newborn showed no evidence of infection or blistering at birth or during the hospital stay.

Figure 1. Periorbital edema with purulent ocular discharge before (A) and after (B) treatment.			Figure 2. Perioral desquamation and radial fissuring before (A) and after (B) treatment.

Staphylococcal scalded skin syndrome is a superficial blistering disorder that ranges in severity from localized blisters to generalized exfoliation.¹ Exfoliative toxin is the major virulence factor responsible for SSSS. Exfoliative toxin is a serine protease that targets desmoglein 1, resulting in intraepidermal separation of keratinocytes.³ Two serologically distinct exfoliative toxins—ETA and ETB—have been associated with human disease.⁴ Although ETA is encoded on a phage genome, ETB is encoded on a large plasmid.³ Initially it was thought that only strains of S aureus carrying lytic group II phages were responsible for ET production; however, it is now accepted that all phage groups are capable of producing ET and causing SSSS.¹

Staphylococcal scalded skin syndrome is most common in infants and children and rare in adults. Although it has been occasionally described in otherwise healthy adults,⁵ it is most often diagnosed in patients with renal failure (decreased toxin excretion), immunodeficiency (lack of antibodies against toxins), and overwhelming staphylococcal infection (excessive toxin).² Mortality in treated children is low, but it can reach almost 60% in adults¹; therefore, defining risk factors that may aid in early diagnosis are exceedingly important.

We believe that both our patient’s history of 
AD and her pregnancy contributed to the development of SSSS. The patient had a history of multiple MRSA infections prior to this hospitalization, suggesting MRSA colonization, which is a common complication of AD with more than 75% of 
AD patients colonized with S aureus.⁶ Additionally, 
S aureus superantigen stimulation can result in the loss of regulatory T cells’ natural immunosuppression. Regulatory T cells are remarkably increased in patients with AD; therefore, the inflammatory response to S aureus is likely amplified in an atopic patient, as there is more native immunosuppressive capacity to be affected.⁴ Furthermore, we believe that pregnancy and its associated immunomodulation is a risk for SSSS. Immune changes in pregnancy are still not well understood; however, it is known that there are alterations to allow symbiosis between the mother and fetus. Anti-ET IgG antibodies are thought to play an important role in protecting against SSSS. Historically, studies on serum immunoglobulin levels during pregnancy have had conflicting findings. They have shown that IgG is either unchanged or decreased, while IgA, IgE, and IgM can be increased, decreased, or unchanged.⁷ In a study of immunoglobulins in pregnancy, Bahna et al⁷ showed that IgE is unchanged over the course of pregnancy, but their analysis did not address IgG levels. If IgG levels in fact decrease during pregnancy, the mother could be at risk for SSSS due to her inability to neutralize toxins. Even if total IgG levels remain unchanged, it is possible that specific antitoxin antibodies are decreased. Additionally, there is a documented suppression and alteration in T-cell response to prevent fetal rejection during pregnancy.⁸ Adult SSSS has been documented several times in human immunodeficiency virus–positive patients, suggesting there may be some association between T-cell suppression and SSSS susceptibility.⁹ Interestingly, pregnancy, similar to AD, results in an increase in immunosuppressive T cells,¹⁰ which, if deactivated by superantigens, could potentially contribute to an increased inflammatory response. All of these immune system alterations likely leave the mother vulnerable to toxin-mediated events such as SSSS.

We believe this case highlights the importance of considering SSSS in both atopic and pregnant patients with desquamating eruptions. In the case of pregnant patients, it is important to consider the risks and benefits of any medical treatments for both the mother and infant. Vancomycin is a pregnancy category B drug and was chosen for its known effectiveness and safety in pregnancy. One study compared 10 babies with mothers who were treated with vancomycin during the second and third trimesters for MRSA to 20 babies with mothers who did not receive vancomycin and did not find an increased risk for sensorineural hearing loss or nephrotoxicity.¹¹ There is no known increased risk for preeclampsia with vancomycin, but some studies have suggested that maternal infection independently increases the risk for preeclampsia.¹² Other treatment options were not as safe as vancomycin in this case: doxycycline is contraindicated (pregnancy category D) due to the potential for staining of deciduous teeth and skeletal growth impairment, trimethoprim-sulfamethoxazole is a pregnancy category D drug during the third trimester due to the risk of kernicterus, and linezolid is a pregnancy category C drug.¹³

Increases in IgA levels were associated with a reduced risk of infections in 84 chronic lymphocytic leukemia (CLL) patients participating in a trial of ibrutinib 420 mg once daily.

After 28 months of ibrutinib treatment, 69 (82%) patients had developed 177 infections. Lower rates of infections were found in those who experienced an IgA increase of at least 50% from their baseline values (P = .03), reported Dr. Clare Sun of the hematology branch of the National Heart, Lung and Blood Institute in Bethesda, Md., and her associates.

At baseline, the patients’ median IgA value was 0.47 g/L; after 6 months of treatment with ibrutinib, the median IgA value was 0.74 g/L. The levels of IgA continued to rise in the next 12 months (n = 43, median increase of 45%, P less than 0001), and patients’ IgA levels at 24 months also were greater than their baseline levels (n = 28, median increase of 64%, P less than .0001).

Using serum-free light chain measures to distinguish clonal and normal B cells, researchers also found recovery of normal B cells and increases in B-cell precursors in bone marrow and in normal B cells in the peripheral blood. This growth, however, was not large enough to raise the majority of patients’ normal B cells to normal levels.

The findings suggest “ibrutinib allows for a clinically meaningful recovery of humoral immune function in patients with CLL,” Dr. Sun and her associates wrote. “The rapidity of increase in IgA suggests that pre-existing antibody-producing cells may be secreting more immunoglobulins, whilst CLL cells, which impair immunoglobulin production, are removed by ibrutinib.”

The patients also had a decline in IgG levels, however, which did not appear to have an adverse impact. The patients’ IgG levels remained stable during the first 6 months of treatment, but by 12 months they had decreased (n = 35, median reduction of 4%, P < .0006), falling further at 24 months (n = 21, median reduction of 23%, P < .0001).

Because ibrutinib may be given indefinitely, extended follow-up is needed to determine the immunologic consequences of prolonged Bruton’s tyrosine kinase inhibition, the researchers wrote.

Read the full study in Blood (2015. doi: 10.1182/blood-2015-04-639203).

[email protected]

Increases in IgA levels were associated with a reduced risk of infections in 84 chronic lymphocytic leukemia (CLL) patients participating in a trial of ibrutinib 420 mg once daily.

After 28 months of ibrutinib treatment, 69 (82%) patients had developed 177 infections. Lower rates of infections were found in those who experienced an IgA increase of at least 50% from their baseline values (P = .03), reported Dr. Clare Sun of the hematology branch of the National Heart, Lung and Blood Institute in Bethesda, Md., and her associates.

At baseline, the patients’ median IgA value was 0.47 g/L; after 6 months of treatment with ibrutinib, the median IgA value was 0.74 g/L. The levels of IgA continued to rise in the next 12 months (n = 43, median increase of 45%, P less than 0001), and patients’ IgA levels at 24 months also were greater than their baseline levels (n = 28, median increase of 64%, P less than .0001).

Using serum-free light chain measures to distinguish clonal and normal B cells, researchers also found recovery of normal B cells and increases in B-cell precursors in bone marrow and in normal B cells in the peripheral blood. This growth, however, was not large enough to raise the majority of patients’ normal B cells to normal levels.

The findings suggest “ibrutinib allows for a clinically meaningful recovery of humoral immune function in patients with CLL,” Dr. Sun and her associates wrote. “The rapidity of increase in IgA suggests that pre-existing antibody-producing cells may be secreting more immunoglobulins, whilst CLL cells, which impair immunoglobulin production, are removed by ibrutinib.”

The patients also had a decline in IgG levels, however, which did not appear to have an adverse impact. The patients’ IgG levels remained stable during the first 6 months of treatment, but by 12 months they had decreased (n = 35, median reduction of 4%, P < .0006), falling further at 24 months (n = 21, median reduction of 23%, P < .0001).

Because ibrutinib may be given indefinitely, extended follow-up is needed to determine the immunologic consequences of prolonged Bruton’s tyrosine kinase inhibition, the researchers wrote.

Read the full study in Blood (2015. doi: 10.1182/blood-2015-04-639203).

[email protected]

Increases in IgA levels were associated with a reduced risk of infections in 84 chronic lymphocytic leukemia (CLL) patients participating in a trial of ibrutinib 420 mg once daily.

After 28 months of ibrutinib treatment, 69 (82%) patients had developed 177 infections. Lower rates of infections were found in those who experienced an IgA increase of at least 50% from their baseline values (P = .03), reported Dr. Clare Sun of the hematology branch of the National Heart, Lung and Blood Institute in Bethesda, Md., and her associates.

At baseline, the patients’ median IgA value was 0.47 g/L; after 6 months of treatment with ibrutinib, the median IgA value was 0.74 g/L. The levels of IgA continued to rise in the next 12 months (n = 43, median increase of 45%, P less than 0001), and patients’ IgA levels at 24 months also were greater than their baseline levels (n = 28, median increase of 64%, P less than .0001).

Using serum-free light chain measures to distinguish clonal and normal B cells, researchers also found recovery of normal B cells and increases in B-cell precursors in bone marrow and in normal B cells in the peripheral blood. This growth, however, was not large enough to raise the majority of patients’ normal B cells to normal levels.

The findings suggest “ibrutinib allows for a clinically meaningful recovery of humoral immune function in patients with CLL,” Dr. Sun and her associates wrote. “The rapidity of increase in IgA suggests that pre-existing antibody-producing cells may be secreting more immunoglobulins, whilst CLL cells, which impair immunoglobulin production, are removed by ibrutinib.”

The patients also had a decline in IgG levels, however, which did not appear to have an adverse impact. The patients’ IgG levels remained stable during the first 6 months of treatment, but by 12 months they had decreased (n = 35, median reduction of 4%, P < .0006), falling further at 24 months (n = 21, median reduction of 23%, P < .0001).

Because ibrutinib may be given indefinitely, extended follow-up is needed to determine the immunologic consequences of prolonged Bruton’s tyrosine kinase inhibition, the researchers wrote.

Read the full study in Blood (2015. doi: 10.1182/blood-2015-04-639203).

[email protected]

Genome sequencing

Photo courtesy of NIGMS

Patients with Sézary syndrome (SS) may have a more complex array of genetic mutations than we thought, according to a paper published in Nature Communications.

Investigators uncovered a genomic landscape that, they believe, can be used to design personalized treatment regimens for SS patients.

In particular, the team found mutations in the JAK/STAT pathway and discovered that JAK-mutated SS cells are sensitive to JAK inhibitors.

To conduct this research, the investigators sequenced SS patient samples using 3 different approaches. They performed whole-genome sequencing (n=6), whole-exome sequencing (n=66), and array comparative genomic hybridization-based copy-number analysis (n=80).

“We basically found chromosomal chaos in all of our samples,” said study author Kojo Elenitoba-Johnson, MD, of the University of Pennsylvania in Philadelphia.

“We did not expect the degree of genetic complexity that we found in our study.”

The investigators identified previously unknown, recurrent, loss-of-function mutations that target genes regulating epigenetic pathways.

One of these targets is ARID1A, and the team found that loss-of-function mutations and/or deletions in ARID1A occurred in more than 40% of the SS genome studied.

The investigators also identified gain-of-function mutations in PLCG1, JAK1, JAK3, STAT3, and STAT5B.

And in preliminary drug-mutation matching studies, JAK1-mutated SS cells were sensitive to JAK inhibitors.

“With knowledge like this, we can design clinical trials using JAK inhibitors for SS patients based on their JAK mutations,” Dr Elenitoba-Johnson said. “But this is just the start. These results highlight the genetic vulnerabilities that we can use in designing precision medicine therapies.”

Now, the investigators want to develop a molecular taxonomy for mutations in SS patients. Using the sequencing technology they used in this study, the team hopes to pinpoint the exact mistakes in each patient’s SS-related genes.

From this, the investigators hope to identify distinct subsets of the disease and stratify patients for precision therapy based on their mutations and the inhibitors available for those mutations.

Genome sequencing

Photo courtesy of NIGMS

Patients with Sézary syndrome (SS) may have a more complex array of genetic mutations than we thought, according to a paper published in Nature Communications.

Investigators uncovered a genomic landscape that, they believe, can be used to design personalized treatment regimens for SS patients.

In particular, the team found mutations in the JAK/STAT pathway and discovered that JAK-mutated SS cells are sensitive to JAK inhibitors.

To conduct this research, the investigators sequenced SS patient samples using 3 different approaches. They performed whole-genome sequencing (n=6), whole-exome sequencing (n=66), and array comparative genomic hybridization-based copy-number analysis (n=80).

“We basically found chromosomal chaos in all of our samples,” said study author Kojo Elenitoba-Johnson, MD, of the University of Pennsylvania in Philadelphia.

“We did not expect the degree of genetic complexity that we found in our study.”

The investigators identified previously unknown, recurrent, loss-of-function mutations that target genes regulating epigenetic pathways.

One of these targets is ARID1A, and the team found that loss-of-function mutations and/or deletions in ARID1A occurred in more than 40% of the SS genome studied.

The investigators also identified gain-of-function mutations in PLCG1, JAK1, JAK3, STAT3, and STAT5B.

And in preliminary drug-mutation matching studies, JAK1-mutated SS cells were sensitive to JAK inhibitors.

“With knowledge like this, we can design clinical trials using JAK inhibitors for SS patients based on their JAK mutations,” Dr Elenitoba-Johnson said. “But this is just the start. These results highlight the genetic vulnerabilities that we can use in designing precision medicine therapies.”

Now, the investigators want to develop a molecular taxonomy for mutations in SS patients. Using the sequencing technology they used in this study, the team hopes to pinpoint the exact mistakes in each patient’s SS-related genes.

From this, the investigators hope to identify distinct subsets of the disease and stratify patients for precision therapy based on their mutations and the inhibitors available for those mutations.

Genome sequencing

Photo courtesy of NIGMS

Patients with Sézary syndrome (SS) may have a more complex array of genetic mutations than we thought, according to a paper published in Nature Communications.

Investigators uncovered a genomic landscape that, they believe, can be used to design personalized treatment regimens for SS patients.

In particular, the team found mutations in the JAK/STAT pathway and discovered that JAK-mutated SS cells are sensitive to JAK inhibitors.

To conduct this research, the investigators sequenced SS patient samples using 3 different approaches. They performed whole-genome sequencing (n=6), whole-exome sequencing (n=66), and array comparative genomic hybridization-based copy-number analysis (n=80).

“We basically found chromosomal chaos in all of our samples,” said study author Kojo Elenitoba-Johnson, MD, of the University of Pennsylvania in Philadelphia.

“We did not expect the degree of genetic complexity that we found in our study.”

The investigators identified previously unknown, recurrent, loss-of-function mutations that target genes regulating epigenetic pathways.

One of these targets is ARID1A, and the team found that loss-of-function mutations and/or deletions in ARID1A occurred in more than 40% of the SS genome studied.

The investigators also identified gain-of-function mutations in PLCG1, JAK1, JAK3, STAT3, and STAT5B.

And in preliminary drug-mutation matching studies, JAK1-mutated SS cells were sensitive to JAK inhibitors.

“With knowledge like this, we can design clinical trials using JAK inhibitors for SS patients based on their JAK mutations,” Dr Elenitoba-Johnson said. “But this is just the start. These results highlight the genetic vulnerabilities that we can use in designing precision medicine therapies.”

Now, the investigators want to develop a molecular taxonomy for mutations in SS patients. Using the sequencing technology they used in this study, the team hopes to pinpoint the exact mistakes in each patient’s SS-related genes.

From this, the investigators hope to identify distinct subsets of the disease and stratify patients for precision therapy based on their mutations and the inhibitors available for those mutations.

Blood for transfusion

Photo courtesy of UAB Hospital

VIENNA—New research suggests that having a higher body mass index (BMI) is associated with a decreased need for blood transfusion among patients undergoing hip or knee replacement surgery.

In this retrospective, single-center study, overweight and obese patients were less likely than patients with a normal BMI to require blood transfusions.

The investigators said these results add to the conflicting body of research examining the association between BMI and blood transfusions in this patient population.

The results were presented at the International Society for Technology in Arthroplasty Annual Congress.

“The results were surprising to us,” said investigator Craig Silverton, DO, of Henry Ford Health System in Detroit, Michigan.

“It goes against the normal thought process. It’s hard to explain, but one theory could be that heavier patients have larger blood volume than patients of normal weight.”

For this study, Dr Silverton and his colleagues evaluated 2399 patients, 1503 of whom underwent knee replacement and 896 of whom underwent hip surgery.

The investigators divided patients into 3 groups according to BMI: normal (BMI less than 25), overweight (BMI of 25 to 29.9), and obese (BMI more than 30).

As BMI increased, there was a significant increase in the estimated blood loss for both types of surgery.

Among hip surgery patients, the estimated blood loss was 268.2± 313.9 mL in patients with a normal BMI, 282.0 ± 208.7 mL in overweight patients, and 330.5 ± 302.4 mL in obese patients.

Among knee surgery patients, the estimated blood loss was 85.7 ± 153.8 mL in patients with a normal BMI, 90.5 ± 164.6 mL in overweight patients, and 89.4 ± 72.4 mL in obese patients.

However, with increasing BMI, there was a significant decrease in the estimated blood volume lost.

Among hip surgery patients, the estimated blood volume lost was 6.12% ± 8.12 in patients with a normal BMI, 4.92% ± 3.05 in overweight patients, and 4.50% ± 3.25 in obese patients.

Among knee surgery patients, the estimated blood volume lost was 2.05% ± 4.00 in patients with a normal BMI, 1.55% ± 2.73 in overweight patients, and 1.26% ± 1.01 in obese patients.

Likewise, there was a significant reduction in transfusion rates as BMI increased.

Among hip surgery patients, the transfusion rate was 34.8% for those with a normal BMI, 27.6% for those who were overweight, and 21.9% for obese patients.

Among knee surgery patients, the transfusion rate was 17.3% for those with a normal BMI, 11.4% for those who were overweight, and 8.3% for obese patients.

The investigators noted that there was no identifiable relationship between BMI and deep vein thrombosis, pulmonary embolism, myocardial infarction, length of hospital stay, 30-day readmission rate, or preoperative hemoglobin level.

There was a trend toward increased deep surgical site infections with increased BMI, but only among patients who underwent hip surgery.

Blood for transfusion

Photo courtesy of UAB Hospital

VIENNA—New research suggests that having a higher body mass index (BMI) is associated with a decreased need for blood transfusion among patients undergoing hip or knee replacement surgery.

In this retrospective, single-center study, overweight and obese patients were less likely than patients with a normal BMI to require blood transfusions.

The investigators said these results add to the conflicting body of research examining the association between BMI and blood transfusions in this patient population.

The results were presented at the International Society for Technology in Arthroplasty Annual Congress.

“The results were surprising to us,” said investigator Craig Silverton, DO, of Henry Ford Health System in Detroit, Michigan.

“It goes against the normal thought process. It’s hard to explain, but one theory could be that heavier patients have larger blood volume than patients of normal weight.”

For this study, Dr Silverton and his colleagues evaluated 2399 patients, 1503 of whom underwent knee replacement and 896 of whom underwent hip surgery.

The investigators divided patients into 3 groups according to BMI: normal (BMI less than 25), overweight (BMI of 25 to 29.9), and obese (BMI more than 30).

As BMI increased, there was a significant increase in the estimated blood loss for both types of surgery.

Among hip surgery patients, the estimated blood loss was 268.2± 313.9 mL in patients with a normal BMI, 282.0 ± 208.7 mL in overweight patients, and 330.5 ± 302.4 mL in obese patients.

Among knee surgery patients, the estimated blood loss was 85.7 ± 153.8 mL in patients with a normal BMI, 90.5 ± 164.6 mL in overweight patients, and 89.4 ± 72.4 mL in obese patients.

However, with increasing BMI, there was a significant decrease in the estimated blood volume lost.

Among hip surgery patients, the estimated blood volume lost was 6.12% ± 8.12 in patients with a normal BMI, 4.92% ± 3.05 in overweight patients, and 4.50% ± 3.25 in obese patients.

Among knee surgery patients, the estimated blood volume lost was 2.05% ± 4.00 in patients with a normal BMI, 1.55% ± 2.73 in overweight patients, and 1.26% ± 1.01 in obese patients.

Likewise, there was a significant reduction in transfusion rates as BMI increased.

Among hip surgery patients, the transfusion rate was 34.8% for those with a normal BMI, 27.6% for those who were overweight, and 21.9% for obese patients.

Among knee surgery patients, the transfusion rate was 17.3% for those with a normal BMI, 11.4% for those who were overweight, and 8.3% for obese patients.

The investigators noted that there was no identifiable relationship between BMI and deep vein thrombosis, pulmonary embolism, myocardial infarction, length of hospital stay, 30-day readmission rate, or preoperative hemoglobin level.

There was a trend toward increased deep surgical site infections with increased BMI, but only among patients who underwent hip surgery.

Blood for transfusion

Photo courtesy of UAB Hospital

VIENNA—New research suggests that having a higher body mass index (BMI) is associated with a decreased need for blood transfusion among patients undergoing hip or knee replacement surgery.

In this retrospective, single-center study, overweight and obese patients were less likely than patients with a normal BMI to require blood transfusions.

The investigators said these results add to the conflicting body of research examining the association between BMI and blood transfusions in this patient population.

The results were presented at the International Society for Technology in Arthroplasty Annual Congress.

“The results were surprising to us,” said investigator Craig Silverton, DO, of Henry Ford Health System in Detroit, Michigan.

“It goes against the normal thought process. It’s hard to explain, but one theory could be that heavier patients have larger blood volume than patients of normal weight.”

For this study, Dr Silverton and his colleagues evaluated 2399 patients, 1503 of whom underwent knee replacement and 896 of whom underwent hip surgery.

The investigators divided patients into 3 groups according to BMI: normal (BMI less than 25), overweight (BMI of 25 to 29.9), and obese (BMI more than 30).

As BMI increased, there was a significant increase in the estimated blood loss for both types of surgery.

Among hip surgery patients, the estimated blood loss was 268.2± 313.9 mL in patients with a normal BMI, 282.0 ± 208.7 mL in overweight patients, and 330.5 ± 302.4 mL in obese patients.

Among knee surgery patients, the estimated blood loss was 85.7 ± 153.8 mL in patients with a normal BMI, 90.5 ± 164.6 mL in overweight patients, and 89.4 ± 72.4 mL in obese patients.

However, with increasing BMI, there was a significant decrease in the estimated blood volume lost.

Among hip surgery patients, the estimated blood volume lost was 6.12% ± 8.12 in patients with a normal BMI, 4.92% ± 3.05 in overweight patients, and 4.50% ± 3.25 in obese patients.

Among knee surgery patients, the estimated blood volume lost was 2.05% ± 4.00 in patients with a normal BMI, 1.55% ± 2.73 in overweight patients, and 1.26% ± 1.01 in obese patients.

Likewise, there was a significant reduction in transfusion rates as BMI increased.

Among hip surgery patients, the transfusion rate was 34.8% for those with a normal BMI, 27.6% for those who were overweight, and 21.9% for obese patients.

Among knee surgery patients, the transfusion rate was 17.3% for those with a normal BMI, 11.4% for those who were overweight, and 8.3% for obese patients.

The investigators noted that there was no identifiable relationship between BMI and deep vein thrombosis, pulmonary embolism, myocardial infarction, length of hospital stay, 30-day readmission rate, or preoperative hemoglobin level.

There was a trend toward increased deep surgical site infections with increased BMI, but only among patients who underwent hip surgery.

DNA repair

Image by Tom Ellenberger

Three researchers have won this year’s Nobel Prize in Chemistry for mechanistic studies of DNA repair.

Tomas Lindahl, MD, PhD, Paul Modrich, PhD, and Aziz Sancar, MD, PhD, each mapped how DNA repair systems function at a detailed molecular level.

Their work has provided insight into how cells function, knowledge that can be used in the development of new cancer treatments, among other applications.

In the early 1970s, scientists believed that DNA was an extremely stable molecule, but Dr Lindahl demonstrated that DNA decays at a rate that ought to have made life on Earth impossible.

This insight led to the discovery of molecular machinery known as base excision repair, which constantly counteracts the collapse of our DNA.

For his part, Dr Sancar mapped nucleotide excision repair, the mechanism that cells use to repair UV damage to DNA.

People born with defects in this repair system will develop skin cancer if they are exposed to sunlight. The cell also utilizes nucleotide excision repair to correct defects caused by mutagenic substances, among other things.

Dr Modrich demonstrated how the cell corrects errors that occur when DNA is replicated during cell division.

This mechanism, mismatch repair, reduces the error frequency during DNA replication by about a thousand-fold. Congenital defects in mismatch repair are known, for example, to cause a hereditary variant of colon cancer.

About the winners

Tomas Lindahl was born in 1938 in Stockholm, Sweden. He earned his PhD in 1967 and his MD in 1970, both from Karolinska Institutet in Sweden. He is currently emeritus group leader at the Francis Crick Institute in London, UK.

Paul Modrich was born in 1946. In 1973, he earned his PhD from Stanford University in California. He is currently an investigator at Howard Hughes Medical Institute in Chevy Chase, Maryland, and a professor at Duke University School of Medicine in Durham, North Carolina.

Aziz Sancar was born in 1946 in Savur, Turkey. He earned his MD in 1969 from Istanbul University in Turkey and his PhD in 1977 from the University of Texas in Dallas. He is currently a professor at the University of North Carolina School of Medicine in Chapel Hill.

DNA repair

Image by Tom Ellenberger

Three researchers have won this year’s Nobel Prize in Chemistry for mechanistic studies of DNA repair.

Tomas Lindahl, MD, PhD, Paul Modrich, PhD, and Aziz Sancar, MD, PhD, each mapped how DNA repair systems function at a detailed molecular level.

Their work has provided insight into how cells function, knowledge that can be used in the development of new cancer treatments, among other applications.

In the early 1970s, scientists believed that DNA was an extremely stable molecule, but Dr Lindahl demonstrated that DNA decays at a rate that ought to have made life on Earth impossible.

This insight led to the discovery of molecular machinery known as base excision repair, which constantly counteracts the collapse of our DNA.

For his part, Dr Sancar mapped nucleotide excision repair, the mechanism that cells use to repair UV damage to DNA.

People born with defects in this repair system will develop skin cancer if they are exposed to sunlight. The cell also utilizes nucleotide excision repair to correct defects caused by mutagenic substances, among other things.

Dr Modrich demonstrated how the cell corrects errors that occur when DNA is replicated during cell division.

This mechanism, mismatch repair, reduces the error frequency during DNA replication by about a thousand-fold. Congenital defects in mismatch repair are known, for example, to cause a hereditary variant of colon cancer.

About the winners

Tomas Lindahl was born in 1938 in Stockholm, Sweden. He earned his PhD in 1967 and his MD in 1970, both from Karolinska Institutet in Sweden. He is currently emeritus group leader at the Francis Crick Institute in London, UK.

Paul Modrich was born in 1946. In 1973, he earned his PhD from Stanford University in California. He is currently an investigator at Howard Hughes Medical Institute in Chevy Chase, Maryland, and a professor at Duke University School of Medicine in Durham, North Carolina.

Aziz Sancar was born in 1946 in Savur, Turkey. He earned his MD in 1969 from Istanbul University in Turkey and his PhD in 1977 from the University of Texas in Dallas. He is currently a professor at the University of North Carolina School of Medicine in Chapel Hill.

DNA repair

Image by Tom Ellenberger

Three researchers have won this year’s Nobel Prize in Chemistry for mechanistic studies of DNA repair.

Tomas Lindahl, MD, PhD, Paul Modrich, PhD, and Aziz Sancar, MD, PhD, each mapped how DNA repair systems function at a detailed molecular level.

Their work has provided insight into how cells function, knowledge that can be used in the development of new cancer treatments, among other applications.

In the early 1970s, scientists believed that DNA was an extremely stable molecule, but Dr Lindahl demonstrated that DNA decays at a rate that ought to have made life on Earth impossible.

This insight led to the discovery of molecular machinery known as base excision repair, which constantly counteracts the collapse of our DNA.

For his part, Dr Sancar mapped nucleotide excision repair, the mechanism that cells use to repair UV damage to DNA.

People born with defects in this repair system will develop skin cancer if they are exposed to sunlight. The cell also utilizes nucleotide excision repair to correct defects caused by mutagenic substances, among other things.

Dr Modrich demonstrated how the cell corrects errors that occur when DNA is replicated during cell division.

This mechanism, mismatch repair, reduces the error frequency during DNA replication by about a thousand-fold. Congenital defects in mismatch repair are known, for example, to cause a hereditary variant of colon cancer.

About the winners

Tomas Lindahl was born in 1938 in Stockholm, Sweden. He earned his PhD in 1967 and his MD in 1970, both from Karolinska Institutet in Sweden. He is currently emeritus group leader at the Francis Crick Institute in London, UK.

Paul Modrich was born in 1946. In 1973, he earned his PhD from Stanford University in California. He is currently an investigator at Howard Hughes Medical Institute in Chevy Chase, Maryland, and a professor at Duke University School of Medicine in Durham, North Carolina.

Aziz Sancar was born in 1946 in Savur, Turkey. He earned his MD in 1969 from Istanbul University in Turkey and his PhD in 1977 from the University of Texas in Dallas. He is currently a professor at the University of North Carolina School of Medicine in Chapel Hill.

Patient’s bone marrow

before (top) and after 7 weeks

of treatment (bottom)

© Knoechel et al.

Results of a case study suggest a gamma-secretase inhibitor (GSI) can be effective against Notch-mutated acute lymphoblastic leukemia (ALL).

The patient, who had early T-cell precursor ALL (ETP-ALL), achieved a complete hematologic response to treatment with BMS-906024, a GSI with anti-Notch

activity.

The patient was then able to proceed to hematopoietic stem cell transplant and was leukemia-free at last follow-up.

The researchers said this suggests that GSIs might hold promise for treating ALL and other cancers characterized by Notch mutations.

Birgit Knoechel, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and her colleagues described this case study in Cold Spring Harbor Molecular Case Studies.

The patient was a 53-year-old male with ETP-ALL who had failed previous rounds of chemotherapy and was then enrolled in a clinical trial of BMS-906024.

The patient began to show immediate improvement after starting treatment with the GSI. After 3 cycles, he went on to transplant and has since been leukemia-free—for 19 months so far.

To determine the genetic basis for the patient’s response to BMS-906024, researchers performed targeted and whole-exome sequencing on his leukemic cells.

They identified 4 potential mutations driving disease progression, including a novel mutation in the NOTCH1 gene that resulted in hyperactive signaling. This mutated gene copy was also duplicated in the cancer genome, resulting in elevated expression.

However, the NOTCH1 mutation, along with 2 of the other mutations, were absent in the remission bone marrow.

The researchers also cultured the patient’s leukemic cells to determine the molecular response to treatment.

Cells treated with BMS-906024 had greatly reduced levels of mutated NOTCH1 protein. RNA sequencing demonstrated that Notch target genes were sensitive to the treatment.

The MYC oncogene, on the other hand, was not sensitive to BMS-906024.

Epigenetic analysis revealed that the enhancer driving MYC expression in the leukemic cells was not Notch-dependent, but rather BRD4-dependent, suggesting another possible therapeutic option for MYC-expressing tumors.

Patient’s bone marrow

before (top) and after 7 weeks

of treatment (bottom)

© Knoechel et al.

Results of a case study suggest a gamma-secretase inhibitor (GSI) can be effective against Notch-mutated acute lymphoblastic leukemia (ALL).

The patient, who had early T-cell precursor ALL (ETP-ALL), achieved a complete hematologic response to treatment with BMS-906024, a GSI with anti-Notch

activity.

The patient was then able to proceed to hematopoietic stem cell transplant and was leukemia-free at last follow-up.

The researchers said this suggests that GSIs might hold promise for treating ALL and other cancers characterized by Notch mutations.

Birgit Knoechel, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and her colleagues described this case study in Cold Spring Harbor Molecular Case Studies.

The patient was a 53-year-old male with ETP-ALL who had failed previous rounds of chemotherapy and was then enrolled in a clinical trial of BMS-906024.

The patient began to show immediate improvement after starting treatment with the GSI. After 3 cycles, he went on to transplant and has since been leukemia-free—for 19 months so far.

To determine the genetic basis for the patient’s response to BMS-906024, researchers performed targeted and whole-exome sequencing on his leukemic cells.

They identified 4 potential mutations driving disease progression, including a novel mutation in the NOTCH1 gene that resulted in hyperactive signaling. This mutated gene copy was also duplicated in the cancer genome, resulting in elevated expression.

However, the NOTCH1 mutation, along with 2 of the other mutations, were absent in the remission bone marrow.

The researchers also cultured the patient’s leukemic cells to determine the molecular response to treatment.

Cells treated with BMS-906024 had greatly reduced levels of mutated NOTCH1 protein. RNA sequencing demonstrated that Notch target genes were sensitive to the treatment.

The MYC oncogene, on the other hand, was not sensitive to BMS-906024.

Epigenetic analysis revealed that the enhancer driving MYC expression in the leukemic cells was not Notch-dependent, but rather BRD4-dependent, suggesting another possible therapeutic option for MYC-expressing tumors.

Patient’s bone marrow

before (top) and after 7 weeks

of treatment (bottom)

© Knoechel et al.

Results of a case study suggest a gamma-secretase inhibitor (GSI) can be effective against Notch-mutated acute lymphoblastic leukemia (ALL).

The patient, who had early T-cell precursor ALL (ETP-ALL), achieved a complete hematologic response to treatment with BMS-906024, a GSI with anti-Notch

activity.

The patient was then able to proceed to hematopoietic stem cell transplant and was leukemia-free at last follow-up.

The researchers said this suggests that GSIs might hold promise for treating ALL and other cancers characterized by Notch mutations.

Birgit Knoechel, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and her colleagues described this case study in Cold Spring Harbor Molecular Case Studies.

The patient was a 53-year-old male with ETP-ALL who had failed previous rounds of chemotherapy and was then enrolled in a clinical trial of BMS-906024.

The patient began to show immediate improvement after starting treatment with the GSI. After 3 cycles, he went on to transplant and has since been leukemia-free—for 19 months so far.

To determine the genetic basis for the patient’s response to BMS-906024, researchers performed targeted and whole-exome sequencing on his leukemic cells.

They identified 4 potential mutations driving disease progression, including a novel mutation in the NOTCH1 gene that resulted in hyperactive signaling. This mutated gene copy was also duplicated in the cancer genome, resulting in elevated expression.

However, the NOTCH1 mutation, along with 2 of the other mutations, were absent in the remission bone marrow.

The researchers also cultured the patient’s leukemic cells to determine the molecular response to treatment.

Cells treated with BMS-906024 had greatly reduced levels of mutated NOTCH1 protein. RNA sequencing demonstrated that Notch target genes were sensitive to the treatment.

The MYC oncogene, on the other hand, was not sensitive to BMS-906024.

Epigenetic analysis revealed that the enhancer driving MYC expression in the leukemic cells was not Notch-dependent, but rather BRD4-dependent, suggesting another possible therapeutic option for MYC-expressing tumors.