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DAPT’s benefit after stroke or TIA clusters in first 21 days
MONTREAL – The optimal length for dual antiplatelet therapy in patients who have just had a mild stroke or transient ischemic attack is 21 days, a duration of combined treatment that maximized protection against major ischemic events while minimizing the extra risk for a major hemorrhage, according to a prespecified analysis of data from the POINT trial.
The POINT (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke) trial randomized 4,881 patients with a very recent mild stroke or transient ischemic attack and without atrial fibrillation to treatment with either clopidogrel plus aspirin or aspirin alone for 90 days. Compared with aspirin alone, dual antiplatelet therapy (DAPT) cut the incidence of a major ischemic event by a relative 25% but also more than doubled the rate of major hemorrhage (New Engl J Med. 2018 Jul 19;377[3]:215-25).
The new, prespecified analysis looked at outcomes on a week-by-week basis over the course of 90 days of treatment, and showed that during the first 21 days the rate of major ischemic events was 5.6% among patients on aspirin only and 3.6% among those on DAPT, a statistically significant 35% relative cut in these adverse outcomes by using DAPT, Jordan J. Elm, PhD, reported at the World Stroke Congress. During the subsequent 69 days on treatment, the incidence of major ischemic events was roughly 1% in both arms of the study, showing that after 3 weeks the incremental benefit from DAPT disappeared, said Dr. Elm, a biostatistician at the Medical University of South Carolina, Charleston.
In contrast, the doubled rate of major hemorrhages (mostly reversible gastrointestinal bleeds) with DAPT, compared with aspirin alone, occurred at a relatively uniform rate throughout the 90 days of treatment, meaning that limiting DAPT to just 21 days could prevent many of the excess hemorrhages.
“These results suggest that limiting clopidogrel plus aspirin use to 21 days may maximize benefit and reduce risk,” Dr. Elm said, especially in light of the findings confirming the efficacy of 21 days of DAPT following a minor stroke or TIA that had been reported several years ago in the CHANCE (Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events) trial (New Engl J Med. 2013 Jul 4;369[1]:11-9).
Although the new finding from the POINT results came in a secondary analysis, it’s statistically legitimate and should be taken into account when writing treatment guidelines, she said, emphasizing that “this is a very important analysis that is not just hypothesis generating.”
Another finding from the new analysis was that a large number of major ischemic events, and hence a large number of the events prevented by DAPT, occurred in the first 2 days following the index event, a finding made possible because the POINT investigators enrolled patients and started treatment within 12 hours of the qualifying events.
“It’s better to start treatment early,” Dr. Elm noted, but she also highlighted that major ischemic events continued to accumulate during days 3-21, suggesting that patients could still benefit from DAPT even if treatment did not start until 24 or 48 hours after their index event.
POINT received no commercial funding aside from study drugs supplied by Sanofi. Dr. Elm reported no disclosures.
SOURCE: Elm JJ et al. World Stroke Congress, Late-breaking session.
The new model using data from the POINT trial confirms what had been previously shown in the CHANCE trial – that 21 days is a sensible cutoff for dual antiplatelet treatment for patients immediately following a mild stroke or transient ischemic attack. Treatment with dual antiplatelet therapy for 21 days provides the same added benefit as 90 days of treatment but with less excess bleeding. The new findings confirm that the CHANCE results were not specific to a Chinese population.
For the time being, clopidogrel is the evidence-based antiplatelet drug to pair with aspirin for this indication. Clopidogrel has the advantages of being generic, cheap, available, and familiar. It’s possible that another P2Y12 inhibitor, such as ticagrelor (Brilinta), might work even better, but that needs to be proven to justify the added expense of a brand-name antiplatelet drug.
Mike Sharma, MD , is a stroke neurologist at McMaster University, Hamilton, Ont. He has been an advisor to Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Janssen Pharmaceuticals, and Pfizer. He made these comments in an interview.
The new model using data from the POINT trial confirms what had been previously shown in the CHANCE trial – that 21 days is a sensible cutoff for dual antiplatelet treatment for patients immediately following a mild stroke or transient ischemic attack. Treatment with dual antiplatelet therapy for 21 days provides the same added benefit as 90 days of treatment but with less excess bleeding. The new findings confirm that the CHANCE results were not specific to a Chinese population.
For the time being, clopidogrel is the evidence-based antiplatelet drug to pair with aspirin for this indication. Clopidogrel has the advantages of being generic, cheap, available, and familiar. It’s possible that another P2Y12 inhibitor, such as ticagrelor (Brilinta), might work even better, but that needs to be proven to justify the added expense of a brand-name antiplatelet drug.
Mike Sharma, MD , is a stroke neurologist at McMaster University, Hamilton, Ont. He has been an advisor to Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Janssen Pharmaceuticals, and Pfizer. He made these comments in an interview.
The new model using data from the POINT trial confirms what had been previously shown in the CHANCE trial – that 21 days is a sensible cutoff for dual antiplatelet treatment for patients immediately following a mild stroke or transient ischemic attack. Treatment with dual antiplatelet therapy for 21 days provides the same added benefit as 90 days of treatment but with less excess bleeding. The new findings confirm that the CHANCE results were not specific to a Chinese population.
For the time being, clopidogrel is the evidence-based antiplatelet drug to pair with aspirin for this indication. Clopidogrel has the advantages of being generic, cheap, available, and familiar. It’s possible that another P2Y12 inhibitor, such as ticagrelor (Brilinta), might work even better, but that needs to be proven to justify the added expense of a brand-name antiplatelet drug.
Mike Sharma, MD , is a stroke neurologist at McMaster University, Hamilton, Ont. He has been an advisor to Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Janssen Pharmaceuticals, and Pfizer. He made these comments in an interview.
MONTREAL – The optimal length for dual antiplatelet therapy in patients who have just had a mild stroke or transient ischemic attack is 21 days, a duration of combined treatment that maximized protection against major ischemic events while minimizing the extra risk for a major hemorrhage, according to a prespecified analysis of data from the POINT trial.
The POINT (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke) trial randomized 4,881 patients with a very recent mild stroke or transient ischemic attack and without atrial fibrillation to treatment with either clopidogrel plus aspirin or aspirin alone for 90 days. Compared with aspirin alone, dual antiplatelet therapy (DAPT) cut the incidence of a major ischemic event by a relative 25% but also more than doubled the rate of major hemorrhage (New Engl J Med. 2018 Jul 19;377[3]:215-25).
The new, prespecified analysis looked at outcomes on a week-by-week basis over the course of 90 days of treatment, and showed that during the first 21 days the rate of major ischemic events was 5.6% among patients on aspirin only and 3.6% among those on DAPT, a statistically significant 35% relative cut in these adverse outcomes by using DAPT, Jordan J. Elm, PhD, reported at the World Stroke Congress. During the subsequent 69 days on treatment, the incidence of major ischemic events was roughly 1% in both arms of the study, showing that after 3 weeks the incremental benefit from DAPT disappeared, said Dr. Elm, a biostatistician at the Medical University of South Carolina, Charleston.
In contrast, the doubled rate of major hemorrhages (mostly reversible gastrointestinal bleeds) with DAPT, compared with aspirin alone, occurred at a relatively uniform rate throughout the 90 days of treatment, meaning that limiting DAPT to just 21 days could prevent many of the excess hemorrhages.
“These results suggest that limiting clopidogrel plus aspirin use to 21 days may maximize benefit and reduce risk,” Dr. Elm said, especially in light of the findings confirming the efficacy of 21 days of DAPT following a minor stroke or TIA that had been reported several years ago in the CHANCE (Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events) trial (New Engl J Med. 2013 Jul 4;369[1]:11-9).
Although the new finding from the POINT results came in a secondary analysis, it’s statistically legitimate and should be taken into account when writing treatment guidelines, she said, emphasizing that “this is a very important analysis that is not just hypothesis generating.”
Another finding from the new analysis was that a large number of major ischemic events, and hence a large number of the events prevented by DAPT, occurred in the first 2 days following the index event, a finding made possible because the POINT investigators enrolled patients and started treatment within 12 hours of the qualifying events.
“It’s better to start treatment early,” Dr. Elm noted, but she also highlighted that major ischemic events continued to accumulate during days 3-21, suggesting that patients could still benefit from DAPT even if treatment did not start until 24 or 48 hours after their index event.
POINT received no commercial funding aside from study drugs supplied by Sanofi. Dr. Elm reported no disclosures.
SOURCE: Elm JJ et al. World Stroke Congress, Late-breaking session.
MONTREAL – The optimal length for dual antiplatelet therapy in patients who have just had a mild stroke or transient ischemic attack is 21 days, a duration of combined treatment that maximized protection against major ischemic events while minimizing the extra risk for a major hemorrhage, according to a prespecified analysis of data from the POINT trial.
The POINT (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke) trial randomized 4,881 patients with a very recent mild stroke or transient ischemic attack and without atrial fibrillation to treatment with either clopidogrel plus aspirin or aspirin alone for 90 days. Compared with aspirin alone, dual antiplatelet therapy (DAPT) cut the incidence of a major ischemic event by a relative 25% but also more than doubled the rate of major hemorrhage (New Engl J Med. 2018 Jul 19;377[3]:215-25).
The new, prespecified analysis looked at outcomes on a week-by-week basis over the course of 90 days of treatment, and showed that during the first 21 days the rate of major ischemic events was 5.6% among patients on aspirin only and 3.6% among those on DAPT, a statistically significant 35% relative cut in these adverse outcomes by using DAPT, Jordan J. Elm, PhD, reported at the World Stroke Congress. During the subsequent 69 days on treatment, the incidence of major ischemic events was roughly 1% in both arms of the study, showing that after 3 weeks the incremental benefit from DAPT disappeared, said Dr. Elm, a biostatistician at the Medical University of South Carolina, Charleston.
In contrast, the doubled rate of major hemorrhages (mostly reversible gastrointestinal bleeds) with DAPT, compared with aspirin alone, occurred at a relatively uniform rate throughout the 90 days of treatment, meaning that limiting DAPT to just 21 days could prevent many of the excess hemorrhages.
“These results suggest that limiting clopidogrel plus aspirin use to 21 days may maximize benefit and reduce risk,” Dr. Elm said, especially in light of the findings confirming the efficacy of 21 days of DAPT following a minor stroke or TIA that had been reported several years ago in the CHANCE (Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events) trial (New Engl J Med. 2013 Jul 4;369[1]:11-9).
Although the new finding from the POINT results came in a secondary analysis, it’s statistically legitimate and should be taken into account when writing treatment guidelines, she said, emphasizing that “this is a very important analysis that is not just hypothesis generating.”
Another finding from the new analysis was that a large number of major ischemic events, and hence a large number of the events prevented by DAPT, occurred in the first 2 days following the index event, a finding made possible because the POINT investigators enrolled patients and started treatment within 12 hours of the qualifying events.
“It’s better to start treatment early,” Dr. Elm noted, but she also highlighted that major ischemic events continued to accumulate during days 3-21, suggesting that patients could still benefit from DAPT even if treatment did not start until 24 or 48 hours after their index event.
POINT received no commercial funding aside from study drugs supplied by Sanofi. Dr. Elm reported no disclosures.
SOURCE: Elm JJ et al. World Stroke Congress, Late-breaking session.
REPORTING FROM THE WORLD STROKE CONGRESS
Key clinical point: All of DAPT’s extra benefit over aspirin alone in recent stroke or transient ischemic attack patients happened during the first 21 days.
Major finding: During the first 21 days, DAPT cut major ischemic events by 35%, compared with aspirin only.
Study details: A prespecified, secondary analysis from POINT, a multicenter, randomized trial with 4,881 patients.
Disclosures: POINT received no commercial funding aside from study drugs supplied by Sanofi. Dr. Elm had no disclosures.
Source: Elm JJ et al. World Stroke Congress, Late-breaking session.
Severe chronic malnutrition: What it is and how to diagnose it
My wife and I have traveled a number of times as far east as Kyrgyzstan and as far south as Paraguay to participate in short 1- to 2-week medical clinics. When I participated in a week-long medical clinic in Haiti in early 2017, the CEO of the hosting U.S. organization asked, “I wonder if we are doing any good here?” His organization had been to Onaville, Haiti for the last 4-5 years.
So my wife Stacy, a retired licensed practical nurse, and I, a general pediatrician with an interest in severe acute malnutrition, went on a 3-month medical sabbatical to Onaville. We were self-funded, with the exception of our home church in Senoia, Ga., paying the cost of our lodging during that time.
Prior to the 2010 Haiti earthquake, the government planned Onaville to be a retirement community area, with a population of only about 1,500, I was told. After the devastating temblor, it became one of several areas where the government sent people displaced from Port-au-Prince. The population today is possibly 250,000 or more.
The poverty in this area has “newer” flavor than areas such as Cité Soleil, which has been there for decades. What we found in Onaville – and probably all of Haiti – is an appalling lack of understanding and appreciation about the nature of malnutrition.
Methods and materials for study
The 1981 World Health Organization’s last printed monograph about severe acute nutrition remains essentially today’s cookbook recipe for treatment. Little seems to have changed since then in the literature I’ve reviewed. It didn’t take long after we started seeing the children in Onaville to shift that interest to something much more serious and widespread.
I wanted to start with basic health assessments in the Onaville children around 5 years and under. These children rarely see a physician, and only about half or so get any vaccine. Most parents do not have any immunization records in their possession to even review.
We decided to measure head size, mid-upper arm circumference, height, weight, and hemoglobin levels. Date of birth was recorded, if known or could at best be closely estimated. Vaccination was recorded as a yes or no response. All children also were examined for evidence of things like swelling, marasmic appearance (wasting, loss of body fat and muscle), yellowed hair, eye findings of vitamin A deficiency, etc. I wanted to get some impression about the health of these children in the same way that most mobile medical clinics do in Haiti.
Being a database programmer since I bought my first computer in 1985, and having written and deployed my office’s current EMR system in 2000, I decided before ever arriving in Haiti to write the software needed for this task. Unlike regular office EMRs, there were some special considerations.
Growth charts needed not only to be generated for individuals, but in aggregate. Hemoglobins levels, too, needed charting. While in the United States, I use Centers for Disease Control and Prevention growth chart data, but for Haiti I used WHO growth data. I was able to procure hemoglobin charting data as well. Aggregate data turned out to be key to our conclusions.
We used a regular consumer quality digital bathroom scale for weights. A sewing tape attached with duct tape to a wall or pillar was used to measure height. Standard head circumference tapes were use to measure heads and arms.
The hemoglobin was measured with a HemoCue Hb 201+ instrument. Size, ruggedness, and cost dictated all our choices because, except for food, we had to carry everything with us. The cost of a new HemoCue was under $400 and each microcuvette test was about $1.50.
Severe anemia
In total, we saw about 386 children, mostly 5 years and under, in Onaville. Toward the end of the 3 months, we were seeing some of those back as follow-ups. One of the first hemoglobins was 4.9 g/dL, with a 5.4 g/dL on repeat. This stunned us. In the first few days, we were seeing what we saw consistently throughout the course of 3 months.
About 19% of these children had hemoglobins from below 9.0 g/dL to below 6 g/dL. More importantly, there was little on physical exam that would trigger one to do a hemoglobin. Low hemoglobins were not associated with yellow-orange hair. No cases of the swelling of kwashiorkor or pencil-like frames of marasmus were seen. 
Severe chronic malnutrition
The scatter charts are very telling and the hemoglobin graphs are explosive. What is demonstrated is that this recent population is slowly starving to death. How can the hemoglobins be so very low in comparison to the only slightly lowered mean averages (the solid red line)?
In over 3 decades of pediatric medicine, I rarely have seen children in the United States with hemoglobins below 9.5 g/dL. Often they have other illnesses that clearly point to the cause. Could the 19% of children with severely lowered hemoglobins (below 9.0 g/dL) be caused by sickle cell disease or something else in these Haitian children?
A search for articles where sickle cell was studied revealed a study done at St. Damien Pediatrics Hospital in Port-au-Prince (Blood. 2012;120:4235). The overall incidence of sickle cell disease was this: “Of the 2,258 samples tested, 247 had HbS, fifty-seven had HbC, ten had HbSS, and three had HbSC.” Only 0.57% of these children had sickle or sickle-C disease where one could expect hemoglobins to be as low as in the children of Onaville. Applying that percentage to the 386 children we saw would account for about only 2 children who might have sickling anemia. Yet we had 73 children in our study with severely lowered hemoglobins below 9.0 g/dL. If you estimate that half of the 250,000 people in Onaville are children, that extrapolates to over 47,000 with severe anemia! I think that a study larger than ours needs to be done to better assess that, however.
My best thought is that these children who have little external evidence of abnormality and mildly lowered growth data represent a type of malnutrition that has not been defined, much less addressed. I call this severe chronic malnutrition. The very low hemoglobins indicate to me that this is not simply a lack of iron – although certainly that is a factor – but rather that these children are in a state of chronic protein deprivation. They represent a large pool of children who exist between those with normal nutritional states and those with the kwashiorkor or marasmus of severe acute malnutrition.
A search of the 69,823 ICD-10 codes in my database for “malnutrition” only turns up the ill-defined terms, “Unspecified severe protein-calorie malnutrition,” “Moderate, and Mild protein-calorie malnutrition,” “Unspecified protein-calorie malnutrition,” and “Sequelae of protein-calorie malnutrition.” Whatever each of those means is purely subjective in my opinion.
Without a clear understanding or definition of what is severe chronic malnutrition, we are like the Titanic trying to avoid icebergs on a moonless night. I think we must define severe chronic malnutrition before we really can understand the pathophysiology and treatment of severe acute malnutrition.
The WHO published its last printed monograph, “The treatment and management of severe acute protein-energy malnutrition,” in 1981. This publication is essentially a cookbook approach for what to do, with no clear presentation of the chemical processes and medicine involved. The primary focus for the WHO is mid-upper arm circumference and weight for height. Reading this document might lead one to believe that all malnutrition is acutely severe. It is most certainly not.
Conclusion
The answer to why some children show the swelling of kwashiorkor and some show marasmus probably will not be found in the study of severe acute malnutrition or refeeding syndrome alone. We must go far beyond the WHO’s cookbook recipe.
I think we must start with the study, definition, and treatment of severe chronic malnutrition.
While in Haiti, we shared these data with three organization that are working to provide nutrition in a starving nation. Together, the Baptist Haiti Mission, Mission of Hope Haiti, and Trinity Hope may well be supplying 175,000 meals a day through school lunches and other avenues throughout the country. Their response was telling. Those at Baptist Haiti Mission, an organization with a presence of almost 80 years there, told us that this information was a “big deal.”
The issue for them is the answer to the question, “How can we tell if we are doing any good in our feeding programs?” A lot of money is being thrown into nutrition without tangible ways to assess impact. Clearly parameters such as mid-upper arm circumference and weight for height that WHO advocates is not adequate, as our plots revealed.
We think that a simple, cheap, hemoglobin finger stick can tell us who is falling through the cracks into severe chronic malnutrition and those at risk for severe acute malnutrition. I am an advocate for instituting hemoglobin surveillance as part of all feeding programs. Then we can come up with the cheapest and most effective in-country mechanisms to treat these children.
Indeed that is our next step in working in Haiti.
Dr. Smith is a board certified pediatrician working in McDonough, Ga., with an interest in malnutrition among the children of Haiti. Email him at [email protected].
My wife and I have traveled a number of times as far east as Kyrgyzstan and as far south as Paraguay to participate in short 1- to 2-week medical clinics. When I participated in a week-long medical clinic in Haiti in early 2017, the CEO of the hosting U.S. organization asked, “I wonder if we are doing any good here?” His organization had been to Onaville, Haiti for the last 4-5 years.
So my wife Stacy, a retired licensed practical nurse, and I, a general pediatrician with an interest in severe acute malnutrition, went on a 3-month medical sabbatical to Onaville. We were self-funded, with the exception of our home church in Senoia, Ga., paying the cost of our lodging during that time.
Prior to the 2010 Haiti earthquake, the government planned Onaville to be a retirement community area, with a population of only about 1,500, I was told. After the devastating temblor, it became one of several areas where the government sent people displaced from Port-au-Prince. The population today is possibly 250,000 or more.
The poverty in this area has “newer” flavor than areas such as Cité Soleil, which has been there for decades. What we found in Onaville – and probably all of Haiti – is an appalling lack of understanding and appreciation about the nature of malnutrition.
Methods and materials for study
The 1981 World Health Organization’s last printed monograph about severe acute nutrition remains essentially today’s cookbook recipe for treatment. Little seems to have changed since then in the literature I’ve reviewed. It didn’t take long after we started seeing the children in Onaville to shift that interest to something much more serious and widespread.
I wanted to start with basic health assessments in the Onaville children around 5 years and under. These children rarely see a physician, and only about half or so get any vaccine. Most parents do not have any immunization records in their possession to even review.
We decided to measure head size, mid-upper arm circumference, height, weight, and hemoglobin levels. Date of birth was recorded, if known or could at best be closely estimated. Vaccination was recorded as a yes or no response. All children also were examined for evidence of things like swelling, marasmic appearance (wasting, loss of body fat and muscle), yellowed hair, eye findings of vitamin A deficiency, etc. I wanted to get some impression about the health of these children in the same way that most mobile medical clinics do in Haiti.
Being a database programmer since I bought my first computer in 1985, and having written and deployed my office’s current EMR system in 2000, I decided before ever arriving in Haiti to write the software needed for this task. Unlike regular office EMRs, there were some special considerations.
Growth charts needed not only to be generated for individuals, but in aggregate. Hemoglobins levels, too, needed charting. While in the United States, I use Centers for Disease Control and Prevention growth chart data, but for Haiti I used WHO growth data. I was able to procure hemoglobin charting data as well. Aggregate data turned out to be key to our conclusions.
We used a regular consumer quality digital bathroom scale for weights. A sewing tape attached with duct tape to a wall or pillar was used to measure height. Standard head circumference tapes were use to measure heads and arms.
The hemoglobin was measured with a HemoCue Hb 201+ instrument. Size, ruggedness, and cost dictated all our choices because, except for food, we had to carry everything with us. The cost of a new HemoCue was under $400 and each microcuvette test was about $1.50.
Severe anemia
In total, we saw about 386 children, mostly 5 years and under, in Onaville. Toward the end of the 3 months, we were seeing some of those back as follow-ups. One of the first hemoglobins was 4.9 g/dL, with a 5.4 g/dL on repeat. This stunned us. In the first few days, we were seeing what we saw consistently throughout the course of 3 months.
About 19% of these children had hemoglobins from below 9.0 g/dL to below 6 g/dL. More importantly, there was little on physical exam that would trigger one to do a hemoglobin. Low hemoglobins were not associated with yellow-orange hair. No cases of the swelling of kwashiorkor or pencil-like frames of marasmus were seen.
Severe chronic malnutrition
The scatter charts are very telling and the hemoglobin graphs are explosive. What is demonstrated is that this recent population is slowly starving to death. How can the hemoglobins be so very low in comparison to the only slightly lowered mean averages (the solid red line)?
In over 3 decades of pediatric medicine, I rarely have seen children in the United States with hemoglobins below 9.5 g/dL. Often they have other illnesses that clearly point to the cause. Could the 19% of children with severely lowered hemoglobins (below 9.0 g/dL) be caused by sickle cell disease or something else in these Haitian children?
A search for articles where sickle cell was studied revealed a study done at St. Damien Pediatrics Hospital in Port-au-Prince (Blood. 2012;120:4235). The overall incidence of sickle cell disease was this: “Of the 2,258 samples tested, 247 had HbS, fifty-seven had HbC, ten had HbSS, and three had HbSC.” Only 0.57% of these children had sickle or sickle-C disease where one could expect hemoglobins to be as low as in the children of Onaville. Applying that percentage to the 386 children we saw would account for about only 2 children who might have sickling anemia. Yet we had 73 children in our study with severely lowered hemoglobins below 9.0 g/dL. If you estimate that half of the 250,000 people in Onaville are children, that extrapolates to over 47,000 with severe anemia! I think that a study larger than ours needs to be done to better assess that, however.
My best thought is that these children who have little external evidence of abnormality and mildly lowered growth data represent a type of malnutrition that has not been defined, much less addressed. I call this severe chronic malnutrition. The very low hemoglobins indicate to me that this is not simply a lack of iron – although certainly that is a factor – but rather that these children are in a state of chronic protein deprivation. They represent a large pool of children who exist between those with normal nutritional states and those with the kwashiorkor or marasmus of severe acute malnutrition.
A search of the 69,823 ICD-10 codes in my database for “malnutrition” only turns up the ill-defined terms, “Unspecified severe protein-calorie malnutrition,” “Moderate, and Mild protein-calorie malnutrition,” “Unspecified protein-calorie malnutrition,” and “Sequelae of protein-calorie malnutrition.” Whatever each of those means is purely subjective in my opinion.
Without a clear understanding or definition of what is severe chronic malnutrition, we are like the Titanic trying to avoid icebergs on a moonless night. I think we must define severe chronic malnutrition before we really can understand the pathophysiology and treatment of severe acute malnutrition.
The WHO published its last printed monograph, “The treatment and management of severe acute protein-energy malnutrition,” in 1981. This publication is essentially a cookbook approach for what to do, with no clear presentation of the chemical processes and medicine involved. The primary focus for the WHO is mid-upper arm circumference and weight for height. Reading this document might lead one to believe that all malnutrition is acutely severe. It is most certainly not.
Conclusion
The answer to why some children show the swelling of kwashiorkor and some show marasmus probably will not be found in the study of severe acute malnutrition or refeeding syndrome alone. We must go far beyond the WHO’s cookbook recipe.
I think we must start with the study, definition, and treatment of severe chronic malnutrition.
While in Haiti, we shared these data with three organization that are working to provide nutrition in a starving nation. Together, the Baptist Haiti Mission, Mission of Hope Haiti, and Trinity Hope may well be supplying 175,000 meals a day through school lunches and other avenues throughout the country. Their response was telling. Those at Baptist Haiti Mission, an organization with a presence of almost 80 years there, told us that this information was a “big deal.”
The issue for them is the answer to the question, “How can we tell if we are doing any good in our feeding programs?” A lot of money is being thrown into nutrition without tangible ways to assess impact. Clearly parameters such as mid-upper arm circumference and weight for height that WHO advocates is not adequate, as our plots revealed.
We think that a simple, cheap, hemoglobin finger stick can tell us who is falling through the cracks into severe chronic malnutrition and those at risk for severe acute malnutrition. I am an advocate for instituting hemoglobin surveillance as part of all feeding programs. Then we can come up with the cheapest and most effective in-country mechanisms to treat these children.
Indeed that is our next step in working in Haiti.
Dr. Smith is a board certified pediatrician working in McDonough, Ga., with an interest in malnutrition among the children of Haiti. Email him at [email protected].
My wife and I have traveled a number of times as far east as Kyrgyzstan and as far south as Paraguay to participate in short 1- to 2-week medical clinics. When I participated in a week-long medical clinic in Haiti in early 2017, the CEO of the hosting U.S. organization asked, “I wonder if we are doing any good here?” His organization had been to Onaville, Haiti for the last 4-5 years.
So my wife Stacy, a retired licensed practical nurse, and I, a general pediatrician with an interest in severe acute malnutrition, went on a 3-month medical sabbatical to Onaville. We were self-funded, with the exception of our home church in Senoia, Ga., paying the cost of our lodging during that time.
Prior to the 2010 Haiti earthquake, the government planned Onaville to be a retirement community area, with a population of only about 1,500, I was told. After the devastating temblor, it became one of several areas where the government sent people displaced from Port-au-Prince. The population today is possibly 250,000 or more.
The poverty in this area has “newer” flavor than areas such as Cité Soleil, which has been there for decades. What we found in Onaville – and probably all of Haiti – is an appalling lack of understanding and appreciation about the nature of malnutrition.
Methods and materials for study
The 1981 World Health Organization’s last printed monograph about severe acute nutrition remains essentially today’s cookbook recipe for treatment. Little seems to have changed since then in the literature I’ve reviewed. It didn’t take long after we started seeing the children in Onaville to shift that interest to something much more serious and widespread.
I wanted to start with basic health assessments in the Onaville children around 5 years and under. These children rarely see a physician, and only about half or so get any vaccine. Most parents do not have any immunization records in their possession to even review.
We decided to measure head size, mid-upper arm circumference, height, weight, and hemoglobin levels. Date of birth was recorded, if known or could at best be closely estimated. Vaccination was recorded as a yes or no response. All children also were examined for evidence of things like swelling, marasmic appearance (wasting, loss of body fat and muscle), yellowed hair, eye findings of vitamin A deficiency, etc. I wanted to get some impression about the health of these children in the same way that most mobile medical clinics do in Haiti.
Being a database programmer since I bought my first computer in 1985, and having written and deployed my office’s current EMR system in 2000, I decided before ever arriving in Haiti to write the software needed for this task. Unlike regular office EMRs, there were some special considerations.
Growth charts needed not only to be generated for individuals, but in aggregate. Hemoglobins levels, too, needed charting. While in the United States, I use Centers for Disease Control and Prevention growth chart data, but for Haiti I used WHO growth data. I was able to procure hemoglobin charting data as well. Aggregate data turned out to be key to our conclusions.
We used a regular consumer quality digital bathroom scale for weights. A sewing tape attached with duct tape to a wall or pillar was used to measure height. Standard head circumference tapes were use to measure heads and arms.
The hemoglobin was measured with a HemoCue Hb 201+ instrument. Size, ruggedness, and cost dictated all our choices because, except for food, we had to carry everything with us. The cost of a new HemoCue was under $400 and each microcuvette test was about $1.50.
Severe anemia
In total, we saw about 386 children, mostly 5 years and under, in Onaville. Toward the end of the 3 months, we were seeing some of those back as follow-ups. One of the first hemoglobins was 4.9 g/dL, with a 5.4 g/dL on repeat. This stunned us. In the first few days, we were seeing what we saw consistently throughout the course of 3 months.
About 19% of these children had hemoglobins from below 9.0 g/dL to below 6 g/dL. More importantly, there was little on physical exam that would trigger one to do a hemoglobin. Low hemoglobins were not associated with yellow-orange hair. No cases of the swelling of kwashiorkor or pencil-like frames of marasmus were seen.
Severe chronic malnutrition
The scatter charts are very telling and the hemoglobin graphs are explosive. What is demonstrated is that this recent population is slowly starving to death. How can the hemoglobins be so very low in comparison to the only slightly lowered mean averages (the solid red line)?
In over 3 decades of pediatric medicine, I rarely have seen children in the United States with hemoglobins below 9.5 g/dL. Often they have other illnesses that clearly point to the cause. Could the 19% of children with severely lowered hemoglobins (below 9.0 g/dL) be caused by sickle cell disease or something else in these Haitian children?
A search for articles where sickle cell was studied revealed a study done at St. Damien Pediatrics Hospital in Port-au-Prince (Blood. 2012;120:4235). The overall incidence of sickle cell disease was this: “Of the 2,258 samples tested, 247 had HbS, fifty-seven had HbC, ten had HbSS, and three had HbSC.” Only 0.57% of these children had sickle or sickle-C disease where one could expect hemoglobins to be as low as in the children of Onaville. Applying that percentage to the 386 children we saw would account for about only 2 children who might have sickling anemia. Yet we had 73 children in our study with severely lowered hemoglobins below 9.0 g/dL. If you estimate that half of the 250,000 people in Onaville are children, that extrapolates to over 47,000 with severe anemia! I think that a study larger than ours needs to be done to better assess that, however.
My best thought is that these children who have little external evidence of abnormality and mildly lowered growth data represent a type of malnutrition that has not been defined, much less addressed. I call this severe chronic malnutrition. The very low hemoglobins indicate to me that this is not simply a lack of iron – although certainly that is a factor – but rather that these children are in a state of chronic protein deprivation. They represent a large pool of children who exist between those with normal nutritional states and those with the kwashiorkor or marasmus of severe acute malnutrition.
A search of the 69,823 ICD-10 codes in my database for “malnutrition” only turns up the ill-defined terms, “Unspecified severe protein-calorie malnutrition,” “Moderate, and Mild protein-calorie malnutrition,” “Unspecified protein-calorie malnutrition,” and “Sequelae of protein-calorie malnutrition.” Whatever each of those means is purely subjective in my opinion.
Without a clear understanding or definition of what is severe chronic malnutrition, we are like the Titanic trying to avoid icebergs on a moonless night. I think we must define severe chronic malnutrition before we really can understand the pathophysiology and treatment of severe acute malnutrition.
The WHO published its last printed monograph, “The treatment and management of severe acute protein-energy malnutrition,” in 1981. This publication is essentially a cookbook approach for what to do, with no clear presentation of the chemical processes and medicine involved. The primary focus for the WHO is mid-upper arm circumference and weight for height. Reading this document might lead one to believe that all malnutrition is acutely severe. It is most certainly not.
Conclusion
The answer to why some children show the swelling of kwashiorkor and some show marasmus probably will not be found in the study of severe acute malnutrition or refeeding syndrome alone. We must go far beyond the WHO’s cookbook recipe.
I think we must start with the study, definition, and treatment of severe chronic malnutrition.
While in Haiti, we shared these data with three organization that are working to provide nutrition in a starving nation. Together, the Baptist Haiti Mission, Mission of Hope Haiti, and Trinity Hope may well be supplying 175,000 meals a day through school lunches and other avenues throughout the country. Their response was telling. Those at Baptist Haiti Mission, an organization with a presence of almost 80 years there, told us that this information was a “big deal.”
The issue for them is the answer to the question, “How can we tell if we are doing any good in our feeding programs?” A lot of money is being thrown into nutrition without tangible ways to assess impact. Clearly parameters such as mid-upper arm circumference and weight for height that WHO advocates is not adequate, as our plots revealed.
We think that a simple, cheap, hemoglobin finger stick can tell us who is falling through the cracks into severe chronic malnutrition and those at risk for severe acute malnutrition. I am an advocate for instituting hemoglobin surveillance as part of all feeding programs. Then we can come up with the cheapest and most effective in-country mechanisms to treat these children.
Indeed that is our next step in working in Haiti.
Dr. Smith is a board certified pediatrician working in McDonough, Ga., with an interest in malnutrition among the children of Haiti. Email him at [email protected].
Jaya Aysola: Gender inclusivity
Dr. Aysola is an assistant professor of medicine and pediatrics at the Perelman School of Medicine. Her primary appointment in the Divisions of General Internal Medicine.
In early August 2018, Dr. Aysola and her colleagues published a qualitative narrative analysis regarding the perceptions of the factors associated with inclusive workplaces in healthcare.
Dr. Aysola is an assistant professor of medicine and pediatrics at the Perelman School of Medicine. Her primary appointment in the Divisions of General Internal Medicine.
In early August 2018, Dr. Aysola and her colleagues published a qualitative narrative analysis regarding the perceptions of the factors associated with inclusive workplaces in healthcare.
Dr. Aysola is an assistant professor of medicine and pediatrics at the Perelman School of Medicine. Her primary appointment in the Divisions of General Internal Medicine.
In early August 2018, Dr. Aysola and her colleagues published a qualitative narrative analysis regarding the perceptions of the factors associated with inclusive workplaces in healthcare.
Study challenges LVEF assessment before DLBCL treatment
Measuring left ventricular ejection fraction (LVEF) before administering doxorubicin-based chemotherapy doesn’t appear to add clinically meaningful information, according to an analysis of diffuse large B-cell lymphoma (DLBCL) patients.
Current guidelines recommend prescreening with either echocardiography or multiple-gated acquisition (MUGA) scan to identify asymptomatic left ventricular dysfunction before administering doxorubicin-containing chemotherapy, since doxorubicin is known for its cardiotoxicity.
But other studies have challenged the usefulness of routine LVEF screening in DLBCL patients.
In the current study, Deborah L. Enns, PhD, and her colleagues at Virginia Mason Medical Center in Seattle reviewed the medical records of 291 patients diagnosed with DLBCL between 2001 and 2013.
In total, 206 patients with normal LVEF and 8 patients with low LVEF received doxorubicin (P = .006). But while that association appears to support routine prescreening to inform clinical decision making, the link disappeared when the researchers factored out previous cardiac disease (P = .51).
“It is possible that previous [heart failure] may have played a larger role in shaping treatment decisions than did LVEF test results alone,” the researchers wrote. The report is in Mayo Clinic Proceedings: Innovations, Quality & Outcomes.
In addition, for patients who had their LVEF measured, the researchers found no difference in posttreatment incidence of heart failure based on whether patients received doxorubicin (7.0%) or did not (6.8%). The same was true for patients with LVEF values of less than 50% before treatment (13% vs. 14%).
The researchers noted that there are several reasons why LVEF prescreening may not be needed before treatment in DLBCL. For instance, DLBCL patients typically receive low cumulative doses of doxorubicin. Also, doxorubicin’s high efficacy in DLBCL should be balanced with the relatively low risk of death from heart failure due to doxorubicin treatment, at around 4% after 5 years for patients without preexisting cardiac conditions.
“We recommend that the policy of routinely performing prescreening LVEF measurements in all patients with DLBCL before administering anthracycline-based chemotherapy treatments be reevaluated,” the researchers wrote.
They reported having no competing interests.
SOURCE: Enns DL et al. Mayo Clin Proc Innov Qual Outcomes. 2018 Aug 3;2(3):277-85.
Measuring left ventricular ejection fraction (LVEF) before administering doxorubicin-based chemotherapy doesn’t appear to add clinically meaningful information, according to an analysis of diffuse large B-cell lymphoma (DLBCL) patients.
Current guidelines recommend prescreening with either echocardiography or multiple-gated acquisition (MUGA) scan to identify asymptomatic left ventricular dysfunction before administering doxorubicin-containing chemotherapy, since doxorubicin is known for its cardiotoxicity.
But other studies have challenged the usefulness of routine LVEF screening in DLBCL patients.
In the current study, Deborah L. Enns, PhD, and her colleagues at Virginia Mason Medical Center in Seattle reviewed the medical records of 291 patients diagnosed with DLBCL between 2001 and 2013.
In total, 206 patients with normal LVEF and 8 patients with low LVEF received doxorubicin (P = .006). But while that association appears to support routine prescreening to inform clinical decision making, the link disappeared when the researchers factored out previous cardiac disease (P = .51).
“It is possible that previous [heart failure] may have played a larger role in shaping treatment decisions than did LVEF test results alone,” the researchers wrote. The report is in Mayo Clinic Proceedings: Innovations, Quality & Outcomes.
In addition, for patients who had their LVEF measured, the researchers found no difference in posttreatment incidence of heart failure based on whether patients received doxorubicin (7.0%) or did not (6.8%). The same was true for patients with LVEF values of less than 50% before treatment (13% vs. 14%).
The researchers noted that there are several reasons why LVEF prescreening may not be needed before treatment in DLBCL. For instance, DLBCL patients typically receive low cumulative doses of doxorubicin. Also, doxorubicin’s high efficacy in DLBCL should be balanced with the relatively low risk of death from heart failure due to doxorubicin treatment, at around 4% after 5 years for patients without preexisting cardiac conditions.
“We recommend that the policy of routinely performing prescreening LVEF measurements in all patients with DLBCL before administering anthracycline-based chemotherapy treatments be reevaluated,” the researchers wrote.
They reported having no competing interests.
SOURCE: Enns DL et al. Mayo Clin Proc Innov Qual Outcomes. 2018 Aug 3;2(3):277-85.
Measuring left ventricular ejection fraction (LVEF) before administering doxorubicin-based chemotherapy doesn’t appear to add clinically meaningful information, according to an analysis of diffuse large B-cell lymphoma (DLBCL) patients.
Current guidelines recommend prescreening with either echocardiography or multiple-gated acquisition (MUGA) scan to identify asymptomatic left ventricular dysfunction before administering doxorubicin-containing chemotherapy, since doxorubicin is known for its cardiotoxicity.
But other studies have challenged the usefulness of routine LVEF screening in DLBCL patients.
In the current study, Deborah L. Enns, PhD, and her colleagues at Virginia Mason Medical Center in Seattle reviewed the medical records of 291 patients diagnosed with DLBCL between 2001 and 2013.
In total, 206 patients with normal LVEF and 8 patients with low LVEF received doxorubicin (P = .006). But while that association appears to support routine prescreening to inform clinical decision making, the link disappeared when the researchers factored out previous cardiac disease (P = .51).
“It is possible that previous [heart failure] may have played a larger role in shaping treatment decisions than did LVEF test results alone,” the researchers wrote. The report is in Mayo Clinic Proceedings: Innovations, Quality & Outcomes.
In addition, for patients who had their LVEF measured, the researchers found no difference in posttreatment incidence of heart failure based on whether patients received doxorubicin (7.0%) or did not (6.8%). The same was true for patients with LVEF values of less than 50% before treatment (13% vs. 14%).
The researchers noted that there are several reasons why LVEF prescreening may not be needed before treatment in DLBCL. For instance, DLBCL patients typically receive low cumulative doses of doxorubicin. Also, doxorubicin’s high efficacy in DLBCL should be balanced with the relatively low risk of death from heart failure due to doxorubicin treatment, at around 4% after 5 years for patients without preexisting cardiac conditions.
“We recommend that the policy of routinely performing prescreening LVEF measurements in all patients with DLBCL before administering anthracycline-based chemotherapy treatments be reevaluated,” the researchers wrote.
They reported having no competing interests.
SOURCE: Enns DL et al. Mayo Clin Proc Innov Qual Outcomes. 2018 Aug 3;2(3):277-85.
FROM MAYO CLINIC PROCEEDINGS: INNOVATIONS, QUALITY & OUTCOMES
Key clinical point:
Major finding: Among diffuse large B-cell lymphoma (DLBCL) patients who had LVEF measured, the incidence of heart failure post treatment did not differ between patients who received doxorubicin and those who did not (P = 1.0).
Study details: A retrospective analysis of 291 patients diagnosed with DLBCL between 2001 and 2013.
Disclosures: The researchers reported having no competing interests.
Source: Enns DL et al. Mayo Clin Proc Innov Qual Outcomes. 2018 Aug 3;2(3):277-85.
Cross-contamination of Pathology Specimens: A Cautionary Tale
Cross-contamination of pathology specimens is a rare but nonnegligible source of potential morbidity in clinical practice. Contaminant tissue fragments, colloquially referred to as floaters, typically are readily identifiable based on obvious cytomorphologic differences, especially if the tissues arise from different organs; however, one cannot rely on such distinctions in a pathology laboratory dedicated to a single organ system (eg, dermatopathology). The inability to identify quickly and confidently the presence of a contaminant puts the patient at risk for misdiagnosis, which can lead to unnecessary morbidity or even mortality in the case of cancer misdiagnosis. Studies that have been conducted to estimate the incidence of this type of error have suggested an overall incidence rate between approximately 1% and 3%.1,2 Awareness of this phenomenon and careful scrutiny when the histopathologic evidence diverges considerably from the clinical impression is critical for minimizing the negative outcomes that could result from the presence of contaminant tissue. We present a case in which cross-contamination of a pathology specimen led to an initial erroneous diagnosis of an aggressive cutaneous melanoma in a patient with a benign adnexal neoplasm.
Case Report
A 72-year-old man was referred to the Pigmented Lesion and Melanoma Program at Stanford University Medical Center and Cancer Institute (Palo Alto, California) for evaluation and treatment of a presumed stage IIB melanoma on the right preauricular cheek based on a shave biopsy that had been performed (<1 month prior) by his local dermatology provider and subsequently read by an affiliated out-of-state dermatopathology laboratory. Per the clinical history that was gathered at the current presentation, neither the patient nor his wife had noticed the lesion prior to his dermatology provider pointing it out on the day of the biopsy. Additionally, he denied associated pain, bleeding, or ulceration. According to outside medical records, the referring dermatology provider described the lesion as a 4-mm pink pearly papule with telangiectasia favoring a diagnosis of basal cell carcinoma, and a diagnostic shave biopsy was performed. On presentation to our clinic, physical examination of the right preauricular cheek revealed a 4×3-mm depressed erythematous scar with no evidence of residual pigmentation or nodularity (Figure 1). There was no clinically appreciable regional lymphadenopathy.
The original dermatopathology report indicated an invasive melanoma with the following pathologic characteristics: superficial spreading type, Breslow depth of at least 2.16 mm, ulceration, and a mitotic index of 8 mitotic figures/mm2 with transection of the invasive component at the peripheral and deep margins. There was no evidence of regression, perineural invasion, lymphovascular invasion, or microsatellites. Interestingly, the report indicated that there also was a basaloid proliferation with features of cylindroma in the same pathology slide adjacent to the aggressive invasive melanoma that was described. Given the complexity of cases referred to our academic center, the standard of care includes internal dermatopathology review of all outside pathology specimens. This review proved critical to this patient’s care in light of the considerable divergence of the initial pathologic diagnosis and the reported clinical features of the lesion.
Internal review of the single pathology slide received from the referring provider showed a total of 4 sections, 3 of which are shown here (Figure 2A). Three sections, including the one not shown, were all consistent with a diagnosis of cylindroma and showed no evidence of a melanocytic proliferation (Figure 2B). However, the fourth section demonstrated marked morphologic dissimilarity compared to the other 3 sections. This outlier section showed a thick cutaneous melanoma with a Breslow depth of at least 2.1 mm, ulceration, a mitotic rate of 12 mitotic figures/mm2, and broad transection of the invasive component at the peripheral and deep margins (Figures 2C and 2D). Correlation with the gross description of tissue processing on the original pathology report indicating that the specimen had been trisected raised suspicion that the fourth and very dissimilar section could be a contaminant from another source that was incorporated into our patient’s histologic sections during processing. Taken together, these discrepancies made the diagnosis of cylindroma alone far more likely than cutaneous melanoma, but we needed conclusive evidence given the dramatic difference in prognosis and management between a cylindroma and an aggressive cutaneous melanoma.
For further diagnostic clarification, we performed polymorphic short tandem repeat (STR) analysis, a well-described forensic pathology technique, to determine if the melanoma and cylindroma specimens derived from different patients, as we hypothesized. This analysis revealed differences in all but one DNA locus tested between the cylindroma specimen and the melanoma specimen, confirming our hypothesis (Figure 3). Subsequent discussion of the case with staff from the dermatopathology laboratory that processed this specimen provided further support for our suspicion that the invasive melanoma specimen was part of a case processed prior to our patient’s benign lesion. Therefore, the wide local excision for treatment of the suspected melanoma fortunately was canceled, and the patient did not require further treatment of the benign cylindroma. The patient expressed relief and gratitude for this critical clarification and change in management.
Comment
Shah et al3 reported a similar case in which a benign granuloma of the lung masqueraded as a squamous cell carcinoma due to histopathologic contamination. Although few similar cases have been described in the literature, the risk posed by such contamination is remarkable, regardless of whether it occurs during specimen grossing, embedding, sectioning, or staining.1,4,5 This risk is amplified in facilities that process specimens originating predominantly from a single organ system or tissue type, as is often the case in dedicated dermatopathology laboratories. In this scenario, it is unlikely that one could use the presence of tissues from 2 different organ systems on a single slide as a way of easily recognizing the presence of a contaminant and rectifying the error. Additionally, the presence of malignant cells in the contaminant further complicates the problem and requires an investigation that can conclusively distinguish the contaminant from the patient’s actual tissue.
In our case, our dermatology and dermatopathology teams partnered with our molecular pathology team to find a solution. Polymorphic STR analysis via polymerase chain reaction amplification is a sensitive method employed commonly in forensic DNA laboratories for determining whether a sample submitted as evidence belongs to a given suspect.6 Although much more commonly used in forensics, STR analysis does have known roles in clinical medicine, such as chimerism testing after bone marrow or allogeneic stem cell transplantation.7 Given the relatively short period of time it takes along with the convenience of commercially available kits, a high discriminative ability, and well-validated interpretation procedures, STR analysis is an excellent method for determining if a given tissue sample came from a given patient, which is what was needed in our case.
The combined clinical, histopathologic, and molecular data in our case allowed for confident clarification of our patient’s diagnosis, sparing him the morbidity of wide local excision on the face, sentinel lymph node biopsy, and emotional distress associated with a diagnosis of aggressive cutaneous melanoma. Our case highlights the critical importance of internal review of pathology specimens in ensuring proper diagnosis and management and reminds us that, though rare, accidental contamination during processing of pathology specimens is a potential adverse event that must be considered, especially when a pathologic finding diverges considerably from what is anticipated based on the patient’s history and physical examination.
Acknowledgment
The authors express gratitude to the patient described herein who graciously provided permission for us to publish his case and clinical photography.
- Gephardt GN, Zarbo RJ. Extraneous tissue in surgical pathology: a College of American Pathologists Q-Probes study of 275 laboratories. Arch Pathol Lab Med. 1996;120:1009-1014.
- Alam M, Shah AD, Ali S, et al. Floaters in Mohs micrographic surgery [published online June 27, 2013]. Dermatol Surg. 2013;39:1317-1322.
- Shah PA, Prat MP, Hostler DC. Benign granuloma masquerading as squamous cell carcinoma due to a “floater.” Hawaii J Med Public Health. 2017;76(11, suppl 2):19-21.
- Platt E, Sommer P, McDonald L, et al. Tissue floaters and contaminants in the histology laboratory. Arch Pathol Lab Med. 2009;133:973-978.
- Layfield LJ, Witt BL, Metzger KG, et al. Extraneous tissue: a potential source for diagnostic error in surgical pathology. Am J Clin Pathol. 2011;136:767-772.
- Butler JM. Forensic DNA testing. Cold Spring Harb Protoc. 2011;2011:1438-1450.
- Manasatienkij C, Ra-ngabpai C. Clinical application of forensic DNA analysis: a literature review. J Med Assoc Thai. 2012;95:1357-1363.
Cross-contamination of pathology specimens is a rare but nonnegligible source of potential morbidity in clinical practice. Contaminant tissue fragments, colloquially referred to as floaters, typically are readily identifiable based on obvious cytomorphologic differences, especially if the tissues arise from different organs; however, one cannot rely on such distinctions in a pathology laboratory dedicated to a single organ system (eg, dermatopathology). The inability to identify quickly and confidently the presence of a contaminant puts the patient at risk for misdiagnosis, which can lead to unnecessary morbidity or even mortality in the case of cancer misdiagnosis. Studies that have been conducted to estimate the incidence of this type of error have suggested an overall incidence rate between approximately 1% and 3%.1,2 Awareness of this phenomenon and careful scrutiny when the histopathologic evidence diverges considerably from the clinical impression is critical for minimizing the negative outcomes that could result from the presence of contaminant tissue. We present a case in which cross-contamination of a pathology specimen led to an initial erroneous diagnosis of an aggressive cutaneous melanoma in a patient with a benign adnexal neoplasm.
Case Report
A 72-year-old man was referred to the Pigmented Lesion and Melanoma Program at Stanford University Medical Center and Cancer Institute (Palo Alto, California) for evaluation and treatment of a presumed stage IIB melanoma on the right preauricular cheek based on a shave biopsy that had been performed (<1 month prior) by his local dermatology provider and subsequently read by an affiliated out-of-state dermatopathology laboratory. Per the clinical history that was gathered at the current presentation, neither the patient nor his wife had noticed the lesion prior to his dermatology provider pointing it out on the day of the biopsy. Additionally, he denied associated pain, bleeding, or ulceration. According to outside medical records, the referring dermatology provider described the lesion as a 4-mm pink pearly papule with telangiectasia favoring a diagnosis of basal cell carcinoma, and a diagnostic shave biopsy was performed. On presentation to our clinic, physical examination of the right preauricular cheek revealed a 4×3-mm depressed erythematous scar with no evidence of residual pigmentation or nodularity (Figure 1). There was no clinically appreciable regional lymphadenopathy.
The original dermatopathology report indicated an invasive melanoma with the following pathologic characteristics: superficial spreading type, Breslow depth of at least 2.16 mm, ulceration, and a mitotic index of 8 mitotic figures/mm2 with transection of the invasive component at the peripheral and deep margins. There was no evidence of regression, perineural invasion, lymphovascular invasion, or microsatellites. Interestingly, the report indicated that there also was a basaloid proliferation with features of cylindroma in the same pathology slide adjacent to the aggressive invasive melanoma that was described. Given the complexity of cases referred to our academic center, the standard of care includes internal dermatopathology review of all outside pathology specimens. This review proved critical to this patient’s care in light of the considerable divergence of the initial pathologic diagnosis and the reported clinical features of the lesion.
Internal review of the single pathology slide received from the referring provider showed a total of 4 sections, 3 of which are shown here (Figure 2A). Three sections, including the one not shown, were all consistent with a diagnosis of cylindroma and showed no evidence of a melanocytic proliferation (Figure 2B). However, the fourth section demonstrated marked morphologic dissimilarity compared to the other 3 sections. This outlier section showed a thick cutaneous melanoma with a Breslow depth of at least 2.1 mm, ulceration, a mitotic rate of 12 mitotic figures/mm2, and broad transection of the invasive component at the peripheral and deep margins (Figures 2C and 2D). Correlation with the gross description of tissue processing on the original pathology report indicating that the specimen had been trisected raised suspicion that the fourth and very dissimilar section could be a contaminant from another source that was incorporated into our patient’s histologic sections during processing. Taken together, these discrepancies made the diagnosis of cylindroma alone far more likely than cutaneous melanoma, but we needed conclusive evidence given the dramatic difference in prognosis and management between a cylindroma and an aggressive cutaneous melanoma.
For further diagnostic clarification, we performed polymorphic short tandem repeat (STR) analysis, a well-described forensic pathology technique, to determine if the melanoma and cylindroma specimens derived from different patients, as we hypothesized. This analysis revealed differences in all but one DNA locus tested between the cylindroma specimen and the melanoma specimen, confirming our hypothesis (Figure 3). Subsequent discussion of the case with staff from the dermatopathology laboratory that processed this specimen provided further support for our suspicion that the invasive melanoma specimen was part of a case processed prior to our patient’s benign lesion. Therefore, the wide local excision for treatment of the suspected melanoma fortunately was canceled, and the patient did not require further treatment of the benign cylindroma. The patient expressed relief and gratitude for this critical clarification and change in management.
Comment
Shah et al3 reported a similar case in which a benign granuloma of the lung masqueraded as a squamous cell carcinoma due to histopathologic contamination. Although few similar cases have been described in the literature, the risk posed by such contamination is remarkable, regardless of whether it occurs during specimen grossing, embedding, sectioning, or staining.1,4,5 This risk is amplified in facilities that process specimens originating predominantly from a single organ system or tissue type, as is often the case in dedicated dermatopathology laboratories. In this scenario, it is unlikely that one could use the presence of tissues from 2 different organ systems on a single slide as a way of easily recognizing the presence of a contaminant and rectifying the error. Additionally, the presence of malignant cells in the contaminant further complicates the problem and requires an investigation that can conclusively distinguish the contaminant from the patient’s actual tissue.
In our case, our dermatology and dermatopathology teams partnered with our molecular pathology team to find a solution. Polymorphic STR analysis via polymerase chain reaction amplification is a sensitive method employed commonly in forensic DNA laboratories for determining whether a sample submitted as evidence belongs to a given suspect.6 Although much more commonly used in forensics, STR analysis does have known roles in clinical medicine, such as chimerism testing after bone marrow or allogeneic stem cell transplantation.7 Given the relatively short period of time it takes along with the convenience of commercially available kits, a high discriminative ability, and well-validated interpretation procedures, STR analysis is an excellent method for determining if a given tissue sample came from a given patient, which is what was needed in our case.
The combined clinical, histopathologic, and molecular data in our case allowed for confident clarification of our patient’s diagnosis, sparing him the morbidity of wide local excision on the face, sentinel lymph node biopsy, and emotional distress associated with a diagnosis of aggressive cutaneous melanoma. Our case highlights the critical importance of internal review of pathology specimens in ensuring proper diagnosis and management and reminds us that, though rare, accidental contamination during processing of pathology specimens is a potential adverse event that must be considered, especially when a pathologic finding diverges considerably from what is anticipated based on the patient’s history and physical examination.
Acknowledgment
The authors express gratitude to the patient described herein who graciously provided permission for us to publish his case and clinical photography.
Cross-contamination of pathology specimens is a rare but nonnegligible source of potential morbidity in clinical practice. Contaminant tissue fragments, colloquially referred to as floaters, typically are readily identifiable based on obvious cytomorphologic differences, especially if the tissues arise from different organs; however, one cannot rely on such distinctions in a pathology laboratory dedicated to a single organ system (eg, dermatopathology). The inability to identify quickly and confidently the presence of a contaminant puts the patient at risk for misdiagnosis, which can lead to unnecessary morbidity or even mortality in the case of cancer misdiagnosis. Studies that have been conducted to estimate the incidence of this type of error have suggested an overall incidence rate between approximately 1% and 3%.1,2 Awareness of this phenomenon and careful scrutiny when the histopathologic evidence diverges considerably from the clinical impression is critical for minimizing the negative outcomes that could result from the presence of contaminant tissue. We present a case in which cross-contamination of a pathology specimen led to an initial erroneous diagnosis of an aggressive cutaneous melanoma in a patient with a benign adnexal neoplasm.
Case Report
A 72-year-old man was referred to the Pigmented Lesion and Melanoma Program at Stanford University Medical Center and Cancer Institute (Palo Alto, California) for evaluation and treatment of a presumed stage IIB melanoma on the right preauricular cheek based on a shave biopsy that had been performed (<1 month prior) by his local dermatology provider and subsequently read by an affiliated out-of-state dermatopathology laboratory. Per the clinical history that was gathered at the current presentation, neither the patient nor his wife had noticed the lesion prior to his dermatology provider pointing it out on the day of the biopsy. Additionally, he denied associated pain, bleeding, or ulceration. According to outside medical records, the referring dermatology provider described the lesion as a 4-mm pink pearly papule with telangiectasia favoring a diagnosis of basal cell carcinoma, and a diagnostic shave biopsy was performed. On presentation to our clinic, physical examination of the right preauricular cheek revealed a 4×3-mm depressed erythematous scar with no evidence of residual pigmentation or nodularity (Figure 1). There was no clinically appreciable regional lymphadenopathy.
The original dermatopathology report indicated an invasive melanoma with the following pathologic characteristics: superficial spreading type, Breslow depth of at least 2.16 mm, ulceration, and a mitotic index of 8 mitotic figures/mm2 with transection of the invasive component at the peripheral and deep margins. There was no evidence of regression, perineural invasion, lymphovascular invasion, or microsatellites. Interestingly, the report indicated that there also was a basaloid proliferation with features of cylindroma in the same pathology slide adjacent to the aggressive invasive melanoma that was described. Given the complexity of cases referred to our academic center, the standard of care includes internal dermatopathology review of all outside pathology specimens. This review proved critical to this patient’s care in light of the considerable divergence of the initial pathologic diagnosis and the reported clinical features of the lesion.
Internal review of the single pathology slide received from the referring provider showed a total of 4 sections, 3 of which are shown here (Figure 2A). Three sections, including the one not shown, were all consistent with a diagnosis of cylindroma and showed no evidence of a melanocytic proliferation (Figure 2B). However, the fourth section demonstrated marked morphologic dissimilarity compared to the other 3 sections. This outlier section showed a thick cutaneous melanoma with a Breslow depth of at least 2.1 mm, ulceration, a mitotic rate of 12 mitotic figures/mm2, and broad transection of the invasive component at the peripheral and deep margins (Figures 2C and 2D). Correlation with the gross description of tissue processing on the original pathology report indicating that the specimen had been trisected raised suspicion that the fourth and very dissimilar section could be a contaminant from another source that was incorporated into our patient’s histologic sections during processing. Taken together, these discrepancies made the diagnosis of cylindroma alone far more likely than cutaneous melanoma, but we needed conclusive evidence given the dramatic difference in prognosis and management between a cylindroma and an aggressive cutaneous melanoma.
For further diagnostic clarification, we performed polymorphic short tandem repeat (STR) analysis, a well-described forensic pathology technique, to determine if the melanoma and cylindroma specimens derived from different patients, as we hypothesized. This analysis revealed differences in all but one DNA locus tested between the cylindroma specimen and the melanoma specimen, confirming our hypothesis (Figure 3). Subsequent discussion of the case with staff from the dermatopathology laboratory that processed this specimen provided further support for our suspicion that the invasive melanoma specimen was part of a case processed prior to our patient’s benign lesion. Therefore, the wide local excision for treatment of the suspected melanoma fortunately was canceled, and the patient did not require further treatment of the benign cylindroma. The patient expressed relief and gratitude for this critical clarification and change in management.
Comment
Shah et al3 reported a similar case in which a benign granuloma of the lung masqueraded as a squamous cell carcinoma due to histopathologic contamination. Although few similar cases have been described in the literature, the risk posed by such contamination is remarkable, regardless of whether it occurs during specimen grossing, embedding, sectioning, or staining.1,4,5 This risk is amplified in facilities that process specimens originating predominantly from a single organ system or tissue type, as is often the case in dedicated dermatopathology laboratories. In this scenario, it is unlikely that one could use the presence of tissues from 2 different organ systems on a single slide as a way of easily recognizing the presence of a contaminant and rectifying the error. Additionally, the presence of malignant cells in the contaminant further complicates the problem and requires an investigation that can conclusively distinguish the contaminant from the patient’s actual tissue.
In our case, our dermatology and dermatopathology teams partnered with our molecular pathology team to find a solution. Polymorphic STR analysis via polymerase chain reaction amplification is a sensitive method employed commonly in forensic DNA laboratories for determining whether a sample submitted as evidence belongs to a given suspect.6 Although much more commonly used in forensics, STR analysis does have known roles in clinical medicine, such as chimerism testing after bone marrow or allogeneic stem cell transplantation.7 Given the relatively short period of time it takes along with the convenience of commercially available kits, a high discriminative ability, and well-validated interpretation procedures, STR analysis is an excellent method for determining if a given tissue sample came from a given patient, which is what was needed in our case.
The combined clinical, histopathologic, and molecular data in our case allowed for confident clarification of our patient’s diagnosis, sparing him the morbidity of wide local excision on the face, sentinel lymph node biopsy, and emotional distress associated with a diagnosis of aggressive cutaneous melanoma. Our case highlights the critical importance of internal review of pathology specimens in ensuring proper diagnosis and management and reminds us that, though rare, accidental contamination during processing of pathology specimens is a potential adverse event that must be considered, especially when a pathologic finding diverges considerably from what is anticipated based on the patient’s history and physical examination.
Acknowledgment
The authors express gratitude to the patient described herein who graciously provided permission for us to publish his case and clinical photography.
- Gephardt GN, Zarbo RJ. Extraneous tissue in surgical pathology: a College of American Pathologists Q-Probes study of 275 laboratories. Arch Pathol Lab Med. 1996;120:1009-1014.
- Alam M, Shah AD, Ali S, et al. Floaters in Mohs micrographic surgery [published online June 27, 2013]. Dermatol Surg. 2013;39:1317-1322.
- Shah PA, Prat MP, Hostler DC. Benign granuloma masquerading as squamous cell carcinoma due to a “floater.” Hawaii J Med Public Health. 2017;76(11, suppl 2):19-21.
- Platt E, Sommer P, McDonald L, et al. Tissue floaters and contaminants in the histology laboratory. Arch Pathol Lab Med. 2009;133:973-978.
- Layfield LJ, Witt BL, Metzger KG, et al. Extraneous tissue: a potential source for diagnostic error in surgical pathology. Am J Clin Pathol. 2011;136:767-772.
- Butler JM. Forensic DNA testing. Cold Spring Harb Protoc. 2011;2011:1438-1450.
- Manasatienkij C, Ra-ngabpai C. Clinical application of forensic DNA analysis: a literature review. J Med Assoc Thai. 2012;95:1357-1363.
- Gephardt GN, Zarbo RJ. Extraneous tissue in surgical pathology: a College of American Pathologists Q-Probes study of 275 laboratories. Arch Pathol Lab Med. 1996;120:1009-1014.
- Alam M, Shah AD, Ali S, et al. Floaters in Mohs micrographic surgery [published online June 27, 2013]. Dermatol Surg. 2013;39:1317-1322.
- Shah PA, Prat MP, Hostler DC. Benign granuloma masquerading as squamous cell carcinoma due to a “floater.” Hawaii J Med Public Health. 2017;76(11, suppl 2):19-21.
- Platt E, Sommer P, McDonald L, et al. Tissue floaters and contaminants in the histology laboratory. Arch Pathol Lab Med. 2009;133:973-978.
- Layfield LJ, Witt BL, Metzger KG, et al. Extraneous tissue: a potential source for diagnostic error in surgical pathology. Am J Clin Pathol. 2011;136:767-772.
- Butler JM. Forensic DNA testing. Cold Spring Harb Protoc. 2011;2011:1438-1450.
- Manasatienkij C, Ra-ngabpai C. Clinical application of forensic DNA analysis: a literature review. J Med Assoc Thai. 2012;95:1357-1363.
Resident Pearl
- Although cross-contamination of pathology specimens is rare, it does occur and can impact diagnosis and management if detected early.
Ultrasound screening improves ovarian cancer survival?
Also today, fat attenuation index boosts coronary CT prognostication, peripheral arterial disease diagnostic tests vary wildly in patients with diabetes, and big drinkers face a new massive health burden.
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Also today, fat attenuation index boosts coronary CT prognostication, peripheral arterial disease diagnostic tests vary wildly in patients with diabetes, and big drinkers face a new massive health burden.
Amazon Alexa
Apple Podcasts
Spotify
Also today, fat attenuation index boosts coronary CT prognostication, peripheral arterial disease diagnostic tests vary wildly in patients with diabetes, and big drinkers face a new massive health burden.
Amazon Alexa
Apple Podcasts
Spotify
Study supports sequencing in kids with cancer
SAN DIEGO—Comprehensive next-generation sequencing is both feasible and clinically useful in pediatric cancer patients, a new study suggests.
Researchers sequenced samples from 253 pediatric cancer patients and found that, in 79% of cases, there was at least one finding that could help guide care.
Scott Newman, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, presented these findings at the American Society of Human Genetics (ASHG) 2018 Annual Meeting (abstract 52).
The researchers conducted whole-genome, exome, and transcriptome sequencing of the patients’ tumors, as well as sequencing non-cancerous tissues from the same patients.
Of the 253 patients studied, 123 had hematologic malignancies.
The researchers found a mean of four pathogenic or likely pathogenic variants per patient (range, 0-18). This included prognostic (21.8%) and diagnostic (15.1%) variants as well as variants that could be targeted therapeutically (6.8%).
In all, 79% of the patients had at least one variant that was targetable, diagnostic, or prognostic. And test results were available within about 40 days, quickly enough that they could be used to guide care.
“With results available in a clinically relevant time frame, and pricing becoming increasingly comparable to the radiology and pathology tests, WGS [whole-genome sequencing] is becoming more accessible to pediatric oncology patients,” Dr. Newman said.
This work was part of the Genomes for Kids study (G4K), an effort to understand how best to use genetic data for pediatric cancer diagnosis and treatment. St. Jude has compiled the information from G4K into a publicly accessible online database.
The researchers have continued to perform sequencing on current patients, and, since the original study ended, have successfully used this method on roughly 300 additional patients. The team plans to continue studying sequencing methods in hopes of producing clinically applicable data more quickly.
G4K was sponsored by St. Jude.
SAN DIEGO—Comprehensive next-generation sequencing is both feasible and clinically useful in pediatric cancer patients, a new study suggests.
Researchers sequenced samples from 253 pediatric cancer patients and found that, in 79% of cases, there was at least one finding that could help guide care.
Scott Newman, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, presented these findings at the American Society of Human Genetics (ASHG) 2018 Annual Meeting (abstract 52).
The researchers conducted whole-genome, exome, and transcriptome sequencing of the patients’ tumors, as well as sequencing non-cancerous tissues from the same patients.
Of the 253 patients studied, 123 had hematologic malignancies.
The researchers found a mean of four pathogenic or likely pathogenic variants per patient (range, 0-18). This included prognostic (21.8%) and diagnostic (15.1%) variants as well as variants that could be targeted therapeutically (6.8%).
In all, 79% of the patients had at least one variant that was targetable, diagnostic, or prognostic. And test results were available within about 40 days, quickly enough that they could be used to guide care.
“With results available in a clinically relevant time frame, and pricing becoming increasingly comparable to the radiology and pathology tests, WGS [whole-genome sequencing] is becoming more accessible to pediatric oncology patients,” Dr. Newman said.
This work was part of the Genomes for Kids study (G4K), an effort to understand how best to use genetic data for pediatric cancer diagnosis and treatment. St. Jude has compiled the information from G4K into a publicly accessible online database.
The researchers have continued to perform sequencing on current patients, and, since the original study ended, have successfully used this method on roughly 300 additional patients. The team plans to continue studying sequencing methods in hopes of producing clinically applicable data more quickly.
G4K was sponsored by St. Jude.
SAN DIEGO—Comprehensive next-generation sequencing is both feasible and clinically useful in pediatric cancer patients, a new study suggests.
Researchers sequenced samples from 253 pediatric cancer patients and found that, in 79% of cases, there was at least one finding that could help guide care.
Scott Newman, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, presented these findings at the American Society of Human Genetics (ASHG) 2018 Annual Meeting (abstract 52).
The researchers conducted whole-genome, exome, and transcriptome sequencing of the patients’ tumors, as well as sequencing non-cancerous tissues from the same patients.
Of the 253 patients studied, 123 had hematologic malignancies.
The researchers found a mean of four pathogenic or likely pathogenic variants per patient (range, 0-18). This included prognostic (21.8%) and diagnostic (15.1%) variants as well as variants that could be targeted therapeutically (6.8%).
In all, 79% of the patients had at least one variant that was targetable, diagnostic, or prognostic. And test results were available within about 40 days, quickly enough that they could be used to guide care.
“With results available in a clinically relevant time frame, and pricing becoming increasingly comparable to the radiology and pathology tests, WGS [whole-genome sequencing] is becoming more accessible to pediatric oncology patients,” Dr. Newman said.
This work was part of the Genomes for Kids study (G4K), an effort to understand how best to use genetic data for pediatric cancer diagnosis and treatment. St. Jude has compiled the information from G4K into a publicly accessible online database.
The researchers have continued to perform sequencing on current patients, and, since the original study ended, have successfully used this method on roughly 300 additional patients. The team plans to continue studying sequencing methods in hopes of producing clinically applicable data more quickly.
G4K was sponsored by St. Jude.
‘Intense’ end-of-life care may be common in HSCT recipients
Patients who die within a year of allogeneic hematopoietic stem cell transplant (HSCT) tend to receive “medically intense” end-of-life care, an analysis suggests.
Researchers studied more than 2,000 patients who died within a year of allogeneic HSCT and found that a majority of the patients died in the hospital, and about half of them were admitted to the intensive care unit (ICU).
However, patient age, underlying diagnosis, and other factors influenced the likelihood of receiving intense end-of-life care.
For example, patients diagnosed with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) were less likely than patients with acute lymphoblastic leukemia (ALL) to receive medically intense care.
Emily Johnston, MD, of the University of Alabama at Birmingham, and her colleagues reported these findings in the Journal of Clinical Oncology.
The researchers studied 2,135 patients in California who underwent inpatient HSCT and died within a year of the transplant (not as a result of peripartum events or trauma) between 2000 and 2013.
Fifty-three percent of the patients received some type of medically intense intervention, and 57% had at least two types of intense interventions.
Eighty-three percent of patients died in hospital, and 43% spent all of their last 30 days in the hospital.
Forty-nine percent of patients were admitted to the ICU, 45% were intubated, 22% underwent hemodialysis, and 8% received cardiopulmonary resuscitation.
Factors associated with intense care
The researchers said receipt of a medically intense intervention varied by age at death, underlying diagnosis, year of HSCT, location of care, and comorbidities. However, use of intense interventions did not vary according to sex, race/ethnicity, insurance type, or income.
Compared to patients age 60 and older, patients in the following age groups were more likely to receive medically intense interventions:
- Ages 15 to 21—odds ratio (OR)=2.6 (P<0.001)
- Ages 30 to 39—OR=1.8 (P<0.01)
- Ages 40 to 49—OR=1.4 (P<0.05).
Patients with comorbidities were more likely to receive intense interventions as well. The OR was 1.6 (P<0.01) for patients with one comorbidity and 2.5 (P<0.001) for patients with two or more comorbidities.
Patients with AML or MDS were less likely than patients with ALL to receive a medically intense intervention—OR=0.7 (P<0.05).
Patients who were transplanted between 2000 and 2004 were less likely to receive an intense intervention than patients transplanted between 2010 and 2013—OR=0.7 (P<0.01).
Patients who changed hospitals between HSCT and death were less likely to receive an intense intervention than patients who stayed at the same hospital. The OR was 0.3 if they transferred to a community hospital and 0.4 if they transferred to a specialty hospital (P<0.001 for both).
Patients living in rural areas were less likely than urban patients to receive a medically intense intervention—OR=0.6 (P<0.05).
“From our data, we understand there is a correlation with high-intensity end-of-life care in patients who die within one year after receiving a stem cell transplant, but we are still unsure if that was the care they wanted,” Dr. Johnston said.
“The findings suggest that, as oncologists, we need to start having end-of-life care conversations earlier with patients to determine if a high-intensity treatment plan is consistent with their goals or if a lower-intensity treatment plan is best. It’s not a one-size-fits-all approach in end-of-life care.”
This research was supported by Stanford University. One study author reported relationships with Corvus Pharmaceuticals, Shire Pharmaceuticals, and Adaptive Biotechnologies. All other authors reported no conflicts.
Patients who die within a year of allogeneic hematopoietic stem cell transplant (HSCT) tend to receive “medically intense” end-of-life care, an analysis suggests.
Researchers studied more than 2,000 patients who died within a year of allogeneic HSCT and found that a majority of the patients died in the hospital, and about half of them were admitted to the intensive care unit (ICU).
However, patient age, underlying diagnosis, and other factors influenced the likelihood of receiving intense end-of-life care.
For example, patients diagnosed with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) were less likely than patients with acute lymphoblastic leukemia (ALL) to receive medically intense care.
Emily Johnston, MD, of the University of Alabama at Birmingham, and her colleagues reported these findings in the Journal of Clinical Oncology.
The researchers studied 2,135 patients in California who underwent inpatient HSCT and died within a year of the transplant (not as a result of peripartum events or trauma) between 2000 and 2013.
Fifty-three percent of the patients received some type of medically intense intervention, and 57% had at least two types of intense interventions.
Eighty-three percent of patients died in hospital, and 43% spent all of their last 30 days in the hospital.
Forty-nine percent of patients were admitted to the ICU, 45% were intubated, 22% underwent hemodialysis, and 8% received cardiopulmonary resuscitation.
Factors associated with intense care
The researchers said receipt of a medically intense intervention varied by age at death, underlying diagnosis, year of HSCT, location of care, and comorbidities. However, use of intense interventions did not vary according to sex, race/ethnicity, insurance type, or income.
Compared to patients age 60 and older, patients in the following age groups were more likely to receive medically intense interventions:
- Ages 15 to 21—odds ratio (OR)=2.6 (P<0.001)
- Ages 30 to 39—OR=1.8 (P<0.01)
- Ages 40 to 49—OR=1.4 (P<0.05).
Patients with comorbidities were more likely to receive intense interventions as well. The OR was 1.6 (P<0.01) for patients with one comorbidity and 2.5 (P<0.001) for patients with two or more comorbidities.
Patients with AML or MDS were less likely than patients with ALL to receive a medically intense intervention—OR=0.7 (P<0.05).
Patients who were transplanted between 2000 and 2004 were less likely to receive an intense intervention than patients transplanted between 2010 and 2013—OR=0.7 (P<0.01).
Patients who changed hospitals between HSCT and death were less likely to receive an intense intervention than patients who stayed at the same hospital. The OR was 0.3 if they transferred to a community hospital and 0.4 if they transferred to a specialty hospital (P<0.001 for both).
Patients living in rural areas were less likely than urban patients to receive a medically intense intervention—OR=0.6 (P<0.05).
“From our data, we understand there is a correlation with high-intensity end-of-life care in patients who die within one year after receiving a stem cell transplant, but we are still unsure if that was the care they wanted,” Dr. Johnston said.
“The findings suggest that, as oncologists, we need to start having end-of-life care conversations earlier with patients to determine if a high-intensity treatment plan is consistent with their goals or if a lower-intensity treatment plan is best. It’s not a one-size-fits-all approach in end-of-life care.”
This research was supported by Stanford University. One study author reported relationships with Corvus Pharmaceuticals, Shire Pharmaceuticals, and Adaptive Biotechnologies. All other authors reported no conflicts.
Patients who die within a year of allogeneic hematopoietic stem cell transplant (HSCT) tend to receive “medically intense” end-of-life care, an analysis suggests.
Researchers studied more than 2,000 patients who died within a year of allogeneic HSCT and found that a majority of the patients died in the hospital, and about half of them were admitted to the intensive care unit (ICU).
However, patient age, underlying diagnosis, and other factors influenced the likelihood of receiving intense end-of-life care.
For example, patients diagnosed with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) were less likely than patients with acute lymphoblastic leukemia (ALL) to receive medically intense care.
Emily Johnston, MD, of the University of Alabama at Birmingham, and her colleagues reported these findings in the Journal of Clinical Oncology.
The researchers studied 2,135 patients in California who underwent inpatient HSCT and died within a year of the transplant (not as a result of peripartum events or trauma) between 2000 and 2013.
Fifty-three percent of the patients received some type of medically intense intervention, and 57% had at least two types of intense interventions.
Eighty-three percent of patients died in hospital, and 43% spent all of their last 30 days in the hospital.
Forty-nine percent of patients were admitted to the ICU, 45% were intubated, 22% underwent hemodialysis, and 8% received cardiopulmonary resuscitation.
Factors associated with intense care
The researchers said receipt of a medically intense intervention varied by age at death, underlying diagnosis, year of HSCT, location of care, and comorbidities. However, use of intense interventions did not vary according to sex, race/ethnicity, insurance type, or income.
Compared to patients age 60 and older, patients in the following age groups were more likely to receive medically intense interventions:
- Ages 15 to 21—odds ratio (OR)=2.6 (P<0.001)
- Ages 30 to 39—OR=1.8 (P<0.01)
- Ages 40 to 49—OR=1.4 (P<0.05).
Patients with comorbidities were more likely to receive intense interventions as well. The OR was 1.6 (P<0.01) for patients with one comorbidity and 2.5 (P<0.001) for patients with two or more comorbidities.
Patients with AML or MDS were less likely than patients with ALL to receive a medically intense intervention—OR=0.7 (P<0.05).
Patients who were transplanted between 2000 and 2004 were less likely to receive an intense intervention than patients transplanted between 2010 and 2013—OR=0.7 (P<0.01).
Patients who changed hospitals between HSCT and death were less likely to receive an intense intervention than patients who stayed at the same hospital. The OR was 0.3 if they transferred to a community hospital and 0.4 if they transferred to a specialty hospital (P<0.001 for both).
Patients living in rural areas were less likely than urban patients to receive a medically intense intervention—OR=0.6 (P<0.05).
“From our data, we understand there is a correlation with high-intensity end-of-life care in patients who die within one year after receiving a stem cell transplant, but we are still unsure if that was the care they wanted,” Dr. Johnston said.
“The findings suggest that, as oncologists, we need to start having end-of-life care conversations earlier with patients to determine if a high-intensity treatment plan is consistent with their goals or if a lower-intensity treatment plan is best. It’s not a one-size-fits-all approach in end-of-life care.”
This research was supported by Stanford University. One study author reported relationships with Corvus Pharmaceuticals, Shire Pharmaceuticals, and Adaptive Biotechnologies. All other authors reported no conflicts.
Adoptive T-cell therapy treats PML
Adoptive T-cell therapy has proven effective for treating progressive multifocal leukoencephalopathy (PML), according to research published in The New England Journal of Medicine.
Researchers observed substantial improvements in three PML patients infused with donor T cells targeting the BK virus.
Although one patient ultimately died, two had complete clearance of the JC virus and no clinical signs of PML after treatment.
“The JC and BK viruses are genetically similar and share proteins that can be targeted by the immune system,” said study author Katy Rezvani, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.
“Because of these similarities, we hypothesized that T cells developed against BK virus may also be effective against JC virus infection.”
Dr. Rezvani’s team developed a novel approach for the generation of BK virus-specific T cells from healthy donors and established a bank of viral-specific T cells for immediate clinical use.
The researchers treated three patients with third-party, partially human leukocyte antigen (HLA)-matched, BK virus-specific T cells.
Patient 1 was a 32-year-old female with acute myeloid leukemia (AML) who previously received a double cord blood transplant.
Patient 2 was a 73-year-old female with JAK2-positive polycythemia rubra vera (PV) who had been treated with ruxolitinib.
Patient 3 was a 35-year-old man with AIDS who had discontinued highly active antiretroviral therapy due to side effects and who was no longer able to walk.
Following the first infusion, all three patients had a reduction in JC viral load in their cerebrospinal fluid. Viral loads dropped from:
- 700 to 78 copies in the AML patient
- 230,000 to 5,200 in the PV patient
- 4,300 to 1,300 in the AIDS patient.
“After infusion of viral-specific T cells, patients 1 and 3 had clinical improvement with significant reduction in JC virus in their cerebrospinal fluid,” Dr. Rezvani said.
“Both patients responded despite persistent T-cell immunodeficiency, supporting the concept that the response was mediated by the adoptively infused viral-specific T cells, and there were no infusion-related reactions.”
The AML patient received two additional infusions, which resulted in clearance of the virus in the cerebrospinal fluid and no signs of PML 27 months after the first infusion.
The PV patient received a second infusion that further reduced JC viral load, but no additional improvement was seen. The patient died 8 months after the first infusion.
The AIDS patient received additional infusions, resulting in complete clearance of the JC virus. This patient has regained mobility, and, 9 months after the first infusion, he is able to walk with a cane.
“We are encouraged that off-the-shelf, third-party, partially HLA-matched BK viral-specific T cells may provide a therapy for PML,” Dr. Rezvani said. “Further study in a larger group of patients is required to determine the success rate, durability, and longer-term adverse events with this treatment.”
This study was supported with funding from the Myelodysplastic Syndromes and Acute Myeloid Leukemia Moon Shot, part of MD Anderson’s Moon Shots Program, as well as the National Institutes of Health.
Adoptive T-cell therapy has proven effective for treating progressive multifocal leukoencephalopathy (PML), according to research published in The New England Journal of Medicine.
Researchers observed substantial improvements in three PML patients infused with donor T cells targeting the BK virus.
Although one patient ultimately died, two had complete clearance of the JC virus and no clinical signs of PML after treatment.
“The JC and BK viruses are genetically similar and share proteins that can be targeted by the immune system,” said study author Katy Rezvani, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.
“Because of these similarities, we hypothesized that T cells developed against BK virus may also be effective against JC virus infection.”
Dr. Rezvani’s team developed a novel approach for the generation of BK virus-specific T cells from healthy donors and established a bank of viral-specific T cells for immediate clinical use.
The researchers treated three patients with third-party, partially human leukocyte antigen (HLA)-matched, BK virus-specific T cells.
Patient 1 was a 32-year-old female with acute myeloid leukemia (AML) who previously received a double cord blood transplant.
Patient 2 was a 73-year-old female with JAK2-positive polycythemia rubra vera (PV) who had been treated with ruxolitinib.
Patient 3 was a 35-year-old man with AIDS who had discontinued highly active antiretroviral therapy due to side effects and who was no longer able to walk.
Following the first infusion, all three patients had a reduction in JC viral load in their cerebrospinal fluid. Viral loads dropped from:
- 700 to 78 copies in the AML patient
- 230,000 to 5,200 in the PV patient
- 4,300 to 1,300 in the AIDS patient.
“After infusion of viral-specific T cells, patients 1 and 3 had clinical improvement with significant reduction in JC virus in their cerebrospinal fluid,” Dr. Rezvani said.
“Both patients responded despite persistent T-cell immunodeficiency, supporting the concept that the response was mediated by the adoptively infused viral-specific T cells, and there were no infusion-related reactions.”
The AML patient received two additional infusions, which resulted in clearance of the virus in the cerebrospinal fluid and no signs of PML 27 months after the first infusion.
The PV patient received a second infusion that further reduced JC viral load, but no additional improvement was seen. The patient died 8 months after the first infusion.
The AIDS patient received additional infusions, resulting in complete clearance of the JC virus. This patient has regained mobility, and, 9 months after the first infusion, he is able to walk with a cane.
“We are encouraged that off-the-shelf, third-party, partially HLA-matched BK viral-specific T cells may provide a therapy for PML,” Dr. Rezvani said. “Further study in a larger group of patients is required to determine the success rate, durability, and longer-term adverse events with this treatment.”
This study was supported with funding from the Myelodysplastic Syndromes and Acute Myeloid Leukemia Moon Shot, part of MD Anderson’s Moon Shots Program, as well as the National Institutes of Health.
Adoptive T-cell therapy has proven effective for treating progressive multifocal leukoencephalopathy (PML), according to research published in The New England Journal of Medicine.
Researchers observed substantial improvements in three PML patients infused with donor T cells targeting the BK virus.
Although one patient ultimately died, two had complete clearance of the JC virus and no clinical signs of PML after treatment.
“The JC and BK viruses are genetically similar and share proteins that can be targeted by the immune system,” said study author Katy Rezvani, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.
“Because of these similarities, we hypothesized that T cells developed against BK virus may also be effective against JC virus infection.”
Dr. Rezvani’s team developed a novel approach for the generation of BK virus-specific T cells from healthy donors and established a bank of viral-specific T cells for immediate clinical use.
The researchers treated three patients with third-party, partially human leukocyte antigen (HLA)-matched, BK virus-specific T cells.
Patient 1 was a 32-year-old female with acute myeloid leukemia (AML) who previously received a double cord blood transplant.
Patient 2 was a 73-year-old female with JAK2-positive polycythemia rubra vera (PV) who had been treated with ruxolitinib.
Patient 3 was a 35-year-old man with AIDS who had discontinued highly active antiretroviral therapy due to side effects and who was no longer able to walk.
Following the first infusion, all three patients had a reduction in JC viral load in their cerebrospinal fluid. Viral loads dropped from:
- 700 to 78 copies in the AML patient
- 230,000 to 5,200 in the PV patient
- 4,300 to 1,300 in the AIDS patient.
“After infusion of viral-specific T cells, patients 1 and 3 had clinical improvement with significant reduction in JC virus in their cerebrospinal fluid,” Dr. Rezvani said.
“Both patients responded despite persistent T-cell immunodeficiency, supporting the concept that the response was mediated by the adoptively infused viral-specific T cells, and there were no infusion-related reactions.”
The AML patient received two additional infusions, which resulted in clearance of the virus in the cerebrospinal fluid and no signs of PML 27 months after the first infusion.
The PV patient received a second infusion that further reduced JC viral load, but no additional improvement was seen. The patient died 8 months after the first infusion.
The AIDS patient received additional infusions, resulting in complete clearance of the JC virus. This patient has regained mobility, and, 9 months after the first infusion, he is able to walk with a cane.
“We are encouraged that off-the-shelf, third-party, partially HLA-matched BK viral-specific T cells may provide a therapy for PML,” Dr. Rezvani said. “Further study in a larger group of patients is required to determine the success rate, durability, and longer-term adverse events with this treatment.”
This study was supported with funding from the Myelodysplastic Syndromes and Acute Myeloid Leukemia Moon Shot, part of MD Anderson’s Moon Shots Program, as well as the National Institutes of Health.
XR-naltrexone beats oral medication for opioid use disorder
Monthly injection is tied to twice rate of treatment retention
Opioid addiction patients given extended-release naltrexone had about twice the rate of treatment retention at 6 months as those given oral naltrexone, a study of 60 adults shows.
“These study findings have immediate clinical relevance for treatment of opioid use disorder, at a time when an opioid epidemic continues unabated in the United States,” wrote Maria A. Sullivan, MD, PhD, of Columbia University, New York, and her colleagues.
Naltrexone remains an alternative to agonist treatment for opioid use disorder, but adherence to a daily pill regimen is often poor. “Extended-release (XR) parenteral formulations of naltrexone, as monthly injection or implants, circumvent the daily pill requirement and have shown promising effectiveness,” the researchers said.
In a study published in the American Journal of Psychiatry, 60 opioid-dependent adults who had completed an inpatient detoxification program were randomized to 50 mg/day of oral naltrexone (or 100 mg on Mondays and Wednesdays and 150 mg on Fridays for those living alone) plus behavior therapy or a 380-mg intramuscular injection of XR-naltrexone monthly plus behavior therapy.
After 6 months, 57% of patients in the XR-naltrexone group were retained in treatment, compared with 28% of the oral group (hazard ratio, 2.18), reported Dr. Sullivan and her colleagues.
A total of 40 adverse events were reported. Insomnia was the most common and occurred in 52% of the patients; it was more common in the oral group, compared with the extended-release group (70% vs. 35%, respectively). A total of nine serious adverse events were reported, and five participants discontinued the study as a result. However, only one event, a case of hives determined to be an allergic reaction, was attributed to the study drug.
The findings were limited by several factors, including the small size, open-label design, and lack of urine data for patients after they discontinued the study, the researchers noted. However, the results “support the use of XR-naltrexone combined with behavioral therapy as an effective treatment for patients seeking opioid withdrawal and nonagonist treatment for preventing relapse to opioid use disorder,” they said. In addition, given the difference in effectiveness and the high risk of a failed treatment with oral naltrexone,” they said.
The study was supported in part by grants from the National Institute on Drug Abuse. Dr. Sullivan had no financial conflicts to disclose.
SOURCE: Sullivan MA et al. Am J Psychiatry. 2018. doi: 10.1176/appi.ajp.2018.17070732.
Monthly injection is tied to twice rate of treatment retention
Monthly injection is tied to twice rate of treatment retention
Opioid addiction patients given extended-release naltrexone had about twice the rate of treatment retention at 6 months as those given oral naltrexone, a study of 60 adults shows.
“These study findings have immediate clinical relevance for treatment of opioid use disorder, at a time when an opioid epidemic continues unabated in the United States,” wrote Maria A. Sullivan, MD, PhD, of Columbia University, New York, and her colleagues.
Naltrexone remains an alternative to agonist treatment for opioid use disorder, but adherence to a daily pill regimen is often poor. “Extended-release (XR) parenteral formulations of naltrexone, as monthly injection or implants, circumvent the daily pill requirement and have shown promising effectiveness,” the researchers said.
In a study published in the American Journal of Psychiatry, 60 opioid-dependent adults who had completed an inpatient detoxification program were randomized to 50 mg/day of oral naltrexone (or 100 mg on Mondays and Wednesdays and 150 mg on Fridays for those living alone) plus behavior therapy or a 380-mg intramuscular injection of XR-naltrexone monthly plus behavior therapy.
After 6 months, 57% of patients in the XR-naltrexone group were retained in treatment, compared with 28% of the oral group (hazard ratio, 2.18), reported Dr. Sullivan and her colleagues.
A total of 40 adverse events were reported. Insomnia was the most common and occurred in 52% of the patients; it was more common in the oral group, compared with the extended-release group (70% vs. 35%, respectively). A total of nine serious adverse events were reported, and five participants discontinued the study as a result. However, only one event, a case of hives determined to be an allergic reaction, was attributed to the study drug.
The findings were limited by several factors, including the small size, open-label design, and lack of urine data for patients after they discontinued the study, the researchers noted. However, the results “support the use of XR-naltrexone combined with behavioral therapy as an effective treatment for patients seeking opioid withdrawal and nonagonist treatment for preventing relapse to opioid use disorder,” they said. In addition, given the difference in effectiveness and the high risk of a failed treatment with oral naltrexone,” they said.
The study was supported in part by grants from the National Institute on Drug Abuse. Dr. Sullivan had no financial conflicts to disclose.
SOURCE: Sullivan MA et al. Am J Psychiatry. 2018. doi: 10.1176/appi.ajp.2018.17070732.
Opioid addiction patients given extended-release naltrexone had about twice the rate of treatment retention at 6 months as those given oral naltrexone, a study of 60 adults shows.
“These study findings have immediate clinical relevance for treatment of opioid use disorder, at a time when an opioid epidemic continues unabated in the United States,” wrote Maria A. Sullivan, MD, PhD, of Columbia University, New York, and her colleagues.
Naltrexone remains an alternative to agonist treatment for opioid use disorder, but adherence to a daily pill regimen is often poor. “Extended-release (XR) parenteral formulations of naltrexone, as monthly injection or implants, circumvent the daily pill requirement and have shown promising effectiveness,” the researchers said.
In a study published in the American Journal of Psychiatry, 60 opioid-dependent adults who had completed an inpatient detoxification program were randomized to 50 mg/day of oral naltrexone (or 100 mg on Mondays and Wednesdays and 150 mg on Fridays for those living alone) plus behavior therapy or a 380-mg intramuscular injection of XR-naltrexone monthly plus behavior therapy.
After 6 months, 57% of patients in the XR-naltrexone group were retained in treatment, compared with 28% of the oral group (hazard ratio, 2.18), reported Dr. Sullivan and her colleagues.
A total of 40 adverse events were reported. Insomnia was the most common and occurred in 52% of the patients; it was more common in the oral group, compared with the extended-release group (70% vs. 35%, respectively). A total of nine serious adverse events were reported, and five participants discontinued the study as a result. However, only one event, a case of hives determined to be an allergic reaction, was attributed to the study drug.
The findings were limited by several factors, including the small size, open-label design, and lack of urine data for patients after they discontinued the study, the researchers noted. However, the results “support the use of XR-naltrexone combined with behavioral therapy as an effective treatment for patients seeking opioid withdrawal and nonagonist treatment for preventing relapse to opioid use disorder,” they said. In addition, given the difference in effectiveness and the high risk of a failed treatment with oral naltrexone,” they said.
The study was supported in part by grants from the National Institute on Drug Abuse. Dr. Sullivan had no financial conflicts to disclose.
SOURCE: Sullivan MA et al. Am J Psychiatry. 2018. doi: 10.1176/appi.ajp.2018.17070732.
FROM THE AMERICAN JOURNAL OF PSYCHIATRY
Key clinical point: Extended-release injected naltrexone retains about twice as many patients in treatment for opioid abuse as oral naltrexone.
Major finding: Significantly more extended-release naltrexone patients remained in treatment, compared with oral naltrexone patients (57% vs. 21%).
Study details: The data come from 60 adults with opioid use disorder who transitioned to outpatient treatment.
Disclosures: The study was supported in part by grants from the National Institute on Drug Abuse. Dr. Sullivan had no financial conflicts to disclose.
Source: Sullivan MA et al. Am J Psychiatry. 2018. doi: 10.1176/appi.ajp.2018.17070732.