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Transcarotid vs. Transfemoral Carotid Artery Stenting in the SVS Vascular Quality Initiative
The Safety and Efficacy Study for Reverse Flow Used during Carotid Artery Stenting Procedure (ROADSTER) multicenter trial reported the lowest stroke rate in high-risk patients compared with any prospective trial of TFCAS, according to Mahmoud B. Malas, MD, of the Johns Hopkins Hospital and his colleagues. However, clinical trials have selection criteria that exclude many patients, and are highly selective of operators performing the procedures, which limit generalizability. Dr. Malas will present a study in Scientific Session S4 that he and his colleagues did to compare in-hospital outcomes after TCAR and TFCAS as reported in VQI.
They analyzed data from the initial 646 patients enrolled in the SVS VQI TCAR Surveillance Project (TSP) and compared it with that of patients who underwent TFCAS between 2005 and 2017. Patients with tandem, traumatic, or dissection lesions were excluded. They used multivariable logistic regression and 1:1 coarsened exact matching (CEM) to analyze neurologic adverse events [stroke and transient ischemic attacks (TIAs)] and in-hospital mortality. Patients in the two procedures were matched on age, race, coronary artery disease, congestive heart failure, prior CABG/PCI, chronic kidney disease, diabetes, ASA class, symptomatic status, restenosis, anatomical and medical risk, emergency status, and preoperative medication use.
Compared with more than 10,000 patients undergoing TFCAS, the 638 undergoing TCAR were significantly older and had more cardiac comorbidities. In contrast, patients in the TFCAS group were more likely to be symptomatic and to have a restenotic lesion. There was no significant change in the odds of stroke/death in TFCAS over the study period.
The rates of in-hospital TIA/stroke as well as TIA/stroke/death were significantly higher in TFCAS compared with TCAR (3.3% vs.1.9% and 3.8% vs.2.2%, respectively; both P = .04). In both procedures, symptomatic patients had higher rates of TIA/stroke/death compared with asymptomatic patients; however, the difference was significant only in the TFCAS (5.3% vs. 2.7%, P less than .001). On multivariable analysis, TFCAS was associated with twice the odds of in-hospital neurologic events and TIA/stroke/death compared with TCAR, independent of symptomatic status. CEM showed similar results.
“Our results show that patients undergoing TCAR had significantly higher medical comorbidities, but half the risk of in-hospital TIA/stroke/death compared to patients undergoing TFCAS. This initial evaluation of VQI TSP demonstrates the ability to rapidly monitor new devices/procedures in real world practice. While preliminary, this is the first study to confirm the benefit of TCAR compared to TFCAS in real-world practice,” Dr. Malas concluded.
Friday, June 22
3:30 - 5 p.m.
HCC, Ballroom A/B
SS24: Transcarotid Artery Revascularization (TCAR) vs. Transfemoral Carotid Artery Stenting (TFCAS) in the SVS Vascular Quality Initiative
The Safety and Efficacy Study for Reverse Flow Used during Carotid Artery Stenting Procedure (ROADSTER) multicenter trial reported the lowest stroke rate in high-risk patients compared with any prospective trial of TFCAS, according to Mahmoud B. Malas, MD, of the Johns Hopkins Hospital and his colleagues. However, clinical trials have selection criteria that exclude many patients, and are highly selective of operators performing the procedures, which limit generalizability. Dr. Malas will present a study in Scientific Session S4 that he and his colleagues did to compare in-hospital outcomes after TCAR and TFCAS as reported in VQI.
They analyzed data from the initial 646 patients enrolled in the SVS VQI TCAR Surveillance Project (TSP) and compared it with that of patients who underwent TFCAS between 2005 and 2017. Patients with tandem, traumatic, or dissection lesions were excluded. They used multivariable logistic regression and 1:1 coarsened exact matching (CEM) to analyze neurologic adverse events [stroke and transient ischemic attacks (TIAs)] and in-hospital mortality. Patients in the two procedures were matched on age, race, coronary artery disease, congestive heart failure, prior CABG/PCI, chronic kidney disease, diabetes, ASA class, symptomatic status, restenosis, anatomical and medical risk, emergency status, and preoperative medication use.
Compared with more than 10,000 patients undergoing TFCAS, the 638 undergoing TCAR were significantly older and had more cardiac comorbidities. In contrast, patients in the TFCAS group were more likely to be symptomatic and to have a restenotic lesion. There was no significant change in the odds of stroke/death in TFCAS over the study period.
The rates of in-hospital TIA/stroke as well as TIA/stroke/death were significantly higher in TFCAS compared with TCAR (3.3% vs.1.9% and 3.8% vs.2.2%, respectively; both P = .04). In both procedures, symptomatic patients had higher rates of TIA/stroke/death compared with asymptomatic patients; however, the difference was significant only in the TFCAS (5.3% vs. 2.7%, P less than .001). On multivariable analysis, TFCAS was associated with twice the odds of in-hospital neurologic events and TIA/stroke/death compared with TCAR, independent of symptomatic status. CEM showed similar results.
“Our results show that patients undergoing TCAR had significantly higher medical comorbidities, but half the risk of in-hospital TIA/stroke/death compared to patients undergoing TFCAS. This initial evaluation of VQI TSP demonstrates the ability to rapidly monitor new devices/procedures in real world practice. While preliminary, this is the first study to confirm the benefit of TCAR compared to TFCAS in real-world practice,” Dr. Malas concluded.
Friday, June 22
3:30 - 5 p.m.
HCC, Ballroom A/B
SS24: Transcarotid Artery Revascularization (TCAR) vs. Transfemoral Carotid Artery Stenting (TFCAS) in the SVS Vascular Quality Initiative
The Safety and Efficacy Study for Reverse Flow Used during Carotid Artery Stenting Procedure (ROADSTER) multicenter trial reported the lowest stroke rate in high-risk patients compared with any prospective trial of TFCAS, according to Mahmoud B. Malas, MD, of the Johns Hopkins Hospital and his colleagues. However, clinical trials have selection criteria that exclude many patients, and are highly selective of operators performing the procedures, which limit generalizability. Dr. Malas will present a study in Scientific Session S4 that he and his colleagues did to compare in-hospital outcomes after TCAR and TFCAS as reported in VQI.
They analyzed data from the initial 646 patients enrolled in the SVS VQI TCAR Surveillance Project (TSP) and compared it with that of patients who underwent TFCAS between 2005 and 2017. Patients with tandem, traumatic, or dissection lesions were excluded. They used multivariable logistic regression and 1:1 coarsened exact matching (CEM) to analyze neurologic adverse events [stroke and transient ischemic attacks (TIAs)] and in-hospital mortality. Patients in the two procedures were matched on age, race, coronary artery disease, congestive heart failure, prior CABG/PCI, chronic kidney disease, diabetes, ASA class, symptomatic status, restenosis, anatomical and medical risk, emergency status, and preoperative medication use.
Compared with more than 10,000 patients undergoing TFCAS, the 638 undergoing TCAR were significantly older and had more cardiac comorbidities. In contrast, patients in the TFCAS group were more likely to be symptomatic and to have a restenotic lesion. There was no significant change in the odds of stroke/death in TFCAS over the study period.
The rates of in-hospital TIA/stroke as well as TIA/stroke/death were significantly higher in TFCAS compared with TCAR (3.3% vs.1.9% and 3.8% vs.2.2%, respectively; both P = .04). In both procedures, symptomatic patients had higher rates of TIA/stroke/death compared with asymptomatic patients; however, the difference was significant only in the TFCAS (5.3% vs. 2.7%, P less than .001). On multivariable analysis, TFCAS was associated with twice the odds of in-hospital neurologic events and TIA/stroke/death compared with TCAR, independent of symptomatic status. CEM showed similar results.
“Our results show that patients undergoing TCAR had significantly higher medical comorbidities, but half the risk of in-hospital TIA/stroke/death compared to patients undergoing TFCAS. This initial evaluation of VQI TSP demonstrates the ability to rapidly monitor new devices/procedures in real world practice. While preliminary, this is the first study to confirm the benefit of TCAR compared to TFCAS in real-world practice,” Dr. Malas concluded.
Friday, June 22
3:30 - 5 p.m.
HCC, Ballroom A/B
SS24: Transcarotid Artery Revascularization (TCAR) vs. Transfemoral Carotid Artery Stenting (TFCAS) in the SVS Vascular Quality Initiative
Herpesvirus infections may have a pathogenic link to Alzheimer’s disease
Two nearly ubiquitous herpes viruses are abundant in the brains of people with Alzheimer’s disease and appear to integrate themselves into the patient’s own genome, where the viruses play havoc with genes involved in Alzheimer’s pathogenesis, among other things, a new study reports.
The genomic analysis of hundreds of Alzheimer’s disease (AD) brain samples found human herpesvirus 6a and 7 (HHV-6a, HHV-7) in the entorhinal cortex and the hippocampus, the initial sites of beta-amyloid overexpression in the disease, first authors Benjamin Readhead, MBBS, Jean-Vianney Haure-Mirande, PhD, and colleagues reported June 21 in Neuron.
The viruses appear to interact with genes implicated in the risk for AD and for regulation and processing of the amyloid precursor protein, including presenilin-1 (PSEN1), BACE1, BIN1, PICALM, and several others. Their presence was directly related to the donors’ Clinical Dementia Rating score, and a mouse model suggests a potential pathway linking HHV infection and brain amyloidosis through a microRNA that’s been previously linked to AD.
It’s impossible to say whether HHV-6a and HHV-7 infections, which occur in nearly 100% of small children, trigger late-life amyloid pathology or whether the viruses reactivate and cross into the brain after amyloid-related damage has already begun, said Keith Fargo, PhD, director of scientific programs and outreach at the Alzheimer’s Association. But the data in this paper are strong enough to give real credence, for the first time, to the idea that Alzheimer’s disease may have an infective component.
“This paper, which is quite dense, presents an idea we have seen before, but which has been mostly dismissed,” Dr. Fargo said in an interview. “For the first time, a world-class group of researchers have completed a landmark paper packed with evidence. It’s not definitive evidence yet, but it will certainly bring that hypothesis into the mainstream in a way it has not been before. The Alzheimer’s research world will sit up and take notice.”
The viruses were present in about 20% of AD brain samples taken from four separate brain banks, but not in control samples or in samples from patients with other neurodegenerative diseases. The commonality suggests that the association is real, and something unique to Alzheimer’s, said Sam Gandy, MD, PhD, one of the paper’s senior authors, and a professor of neurology at Mount Sinai Medical Center, New York.
Joel T. Dudley, PhD, director of the Mount Sinai Institute for Next Generation Healthcare, was the other senior author.
“It seems obvious to us that the AD brains around this country are accumulating the genomes of this particular pair of viruses,” Dr. Gandy said in an interview. “For whatever reason, these people were accumulating the genomes of an infectious agent which crossed the blood-brain barrier, went into the brain, and was present there when they were dying of AD. It was not a remote relationship, such as we would see with serology. This was there when they were dying, and it’s hard to imagine it was doing anything good.”
HHV6 causes a primary illness – roseola – when it first enters the body, usually in early childhood. It then enters a life-long latency, but can reactivate in adulthood, according to the HHV-6 Foundation.
“Reactivation can occur in the brain, lungs, heart, kidney, and gastrointestinal tract, especially in patients with immune deficiencies and transplant patients. In some cases, HHV-6 reactivation in the brain tissue can cause cognitive dysfunction, permanent disability, and death.”
The Neuron paper describes several separate investigations that led the team to conclude that HHV-6a and HHV-7 may be implicated in AD pathogenesis.
Dr. Gandy, Dr. Dudley, and their team were not looking for potentially infective agents when they started down this road 5 years ago. Instead, they wanted to see how genes and gene networks change as patients progress from preclinical Alzheimer’s to Alzheimer’s dementia, in the hope of finding novel drug targets.
“This was a surprise result. We were looking for genes differentially expressed as AD progressed. Instead, we found gene expression changes associated with viral infections.”
A transcriptome analysis pointed to microRNA-155, a molecule that helps control viral infections. This lead the team to look for viral RNA in 643 brain samples from the Mount Sinai Brain Bank. “What we found was that HHV-6a and HHV-7 appeared to be driving these changes,” Dr. Gandy said.
HHV-6a interacted with some of the most well-known AD risk genes, Dr. Gandy said.
“The story is full of tantalizing, yet not quite definitive pieces. Presenilin 1 is the most common cause of genetic forms of AD. There are about two dozen genes associated with late-onset sporadic AD. As we scrutinized the computational analysis of the data, whom should we find lurking there among the genes regulated by HHV-6a and HHV-7 but several of our old gene friends from conventional AD genetics and genome-wide association studies: PSEN1, BIN1, PICALM, among others, all of which are linked to causing AD.”
They validated the results from the Mount Sinai Brain Bank in three other data sets: the Religious Orders Study (300 samples from AD patients and healthy controls) the Rush Memory and Aging Project (298 samples from AD patients and healthy controls), and a collection of temporal cortex studies from the Mayo Clinic (278 samples from patients with AD, pathological aging, or progressive supranuclear palsy, and healthy controls).
Again, they saw HHV-6a and HHV-7 in the AD samples, but not in the normal controls or those with pathological aging. Compared with the AD samples, HHV-7 was present in the progressive supranuclear palsy samples, but HHV-6a was reduced.
Whole-exome sequencing found HHV-6a DNA integrated into host DNA. “This may indicate that the HHV-6a DNA that we find as more abundant in AD reflects HHV-6A that has undergone reactivation from a chromosomally integrated form, although we have not evaluated this directly,” Dr. Readhead and his co-investigators wrote in the paper.
Dr. Gandy said that the presence of the two viruses correlated directly with the patients’ Clinical Dementia Rating scale score, neuritic plaque density across multiple regions, and Braak stage, a measure of neurofibrillary tangles.
Another investigation looked at the fractions of the four major brain cells (neurons, astrocytes, microglia, and endothelial cells) and their relationship to viral RNA. HHV-6a was associated with decreases in the neuronal content of fractions from multiple brain regions, and in all four datasets.
Dr. Haure-Mirande and the team also studied a mouse model lacking the virus-suppressing microRNA-155 molecule and crossed this with one of the most commonly used AD research strains that overexpresses human amyloid precursor protein and develops brain amyloidosis. At 4 months, these mice had larger, more frequent amyloid plaques than the standard amyloidosis mice. Cortical RNA sequencing revealed overlap between upregulated genes in the microRNA-155 knockout mice and the HHV-6a–upregulated genes in human brains.
“These findings support the view of microRNA-155 as a regulator of complex anti- and pro-viral actions, offer a mechanism linking viral activity with AD pathology, and support the hypothesis that viral activity contributes to AD,” the investigators wrote.
As Dr. Gandy said, while not definitive, the studies are tantalizing and lay a solid framework for further investigation. He is confident enough about the association to view HHV as a potential therapeutic target for AD.
“The first step is to find a way to detect the viruses in people. We do have our first antibody to recognize one of the viral proteins, so we’re about to test that on blood serum, blood cells, and spinal fluid, and we will also look for viral DNA in the blood cells. Potentially – way down the road – we might be able to conduct a trial using antivirals,” to see if treatment could slow, or prevent, Alzheimer’s progression.
“These are nice, discrete, testable hypotheses, which makes them attractive,” Dr. Gandy said, “but the truth could be different and is almost certainly a lot messier.”
Dr. Gandy has received research funding from Baxter and Amicus Therapeutics, and personal remuneration from Pfizer and DiaGenic.
SOURCE: Readhead B et al. Neuron. 2018 June 21. doi: 10.1016/j.neuron.2018.05.023.
The study by Readhead and colleagues is a scientific tour de force and is likely to elevate the infective hypothesis to a greater height than ever before and deservedly so. Still, the findings are puzzling, at least to this relative virologic novice.
The relationship of infective agents with seemingly degenerative brain diseases has been a complex puzzle that has led to at least two major discoveries. First was the description of a lifeform simpler than viruses, the prion and identification of the human PrP gene that when mutated is the cause of familial Creutzfeldt-Jakob disease (CJD), which can also be transmitted from human to human (or human to monkey) via tissue transplants.
The data provided by Readhead and colleagues are compelling, however, and unquestionably deserve further attention. Where this will lead is still too early to tell, but given the failure of existing paradigms to translate into meaningful disease-modifying therapies, we have new reason to hope that such a therapy may yet be possible in our lifetime.
Richard J. Caselli, MD, is a professor of neurology at the Mayo Clinic Arizona in Scottsdale and is also associate director and clinical core director of the Arizona Alzheimer’s Disease Center.
The study by Readhead and colleagues is a scientific tour de force and is likely to elevate the infective hypothesis to a greater height than ever before and deservedly so. Still, the findings are puzzling, at least to this relative virologic novice.
The relationship of infective agents with seemingly degenerative brain diseases has been a complex puzzle that has led to at least two major discoveries. First was the description of a lifeform simpler than viruses, the prion and identification of the human PrP gene that when mutated is the cause of familial Creutzfeldt-Jakob disease (CJD), which can also be transmitted from human to human (or human to monkey) via tissue transplants.
The data provided by Readhead and colleagues are compelling, however, and unquestionably deserve further attention. Where this will lead is still too early to tell, but given the failure of existing paradigms to translate into meaningful disease-modifying therapies, we have new reason to hope that such a therapy may yet be possible in our lifetime.
Richard J. Caselli, MD, is a professor of neurology at the Mayo Clinic Arizona in Scottsdale and is also associate director and clinical core director of the Arizona Alzheimer’s Disease Center.
The study by Readhead and colleagues is a scientific tour de force and is likely to elevate the infective hypothesis to a greater height than ever before and deservedly so. Still, the findings are puzzling, at least to this relative virologic novice.
The relationship of infective agents with seemingly degenerative brain diseases has been a complex puzzle that has led to at least two major discoveries. First was the description of a lifeform simpler than viruses, the prion and identification of the human PrP gene that when mutated is the cause of familial Creutzfeldt-Jakob disease (CJD), which can also be transmitted from human to human (or human to monkey) via tissue transplants.
The data provided by Readhead and colleagues are compelling, however, and unquestionably deserve further attention. Where this will lead is still too early to tell, but given the failure of existing paradigms to translate into meaningful disease-modifying therapies, we have new reason to hope that such a therapy may yet be possible in our lifetime.
Richard J. Caselli, MD, is a professor of neurology at the Mayo Clinic Arizona in Scottsdale and is also associate director and clinical core director of the Arizona Alzheimer’s Disease Center.
Two nearly ubiquitous herpes viruses are abundant in the brains of people with Alzheimer’s disease and appear to integrate themselves into the patient’s own genome, where the viruses play havoc with genes involved in Alzheimer’s pathogenesis, among other things, a new study reports.
The genomic analysis of hundreds of Alzheimer’s disease (AD) brain samples found human herpesvirus 6a and 7 (HHV-6a, HHV-7) in the entorhinal cortex and the hippocampus, the initial sites of beta-amyloid overexpression in the disease, first authors Benjamin Readhead, MBBS, Jean-Vianney Haure-Mirande, PhD, and colleagues reported June 21 in Neuron.
The viruses appear to interact with genes implicated in the risk for AD and for regulation and processing of the amyloid precursor protein, including presenilin-1 (PSEN1), BACE1, BIN1, PICALM, and several others. Their presence was directly related to the donors’ Clinical Dementia Rating score, and a mouse model suggests a potential pathway linking HHV infection and brain amyloidosis through a microRNA that’s been previously linked to AD.
It’s impossible to say whether HHV-6a and HHV-7 infections, which occur in nearly 100% of small children, trigger late-life amyloid pathology or whether the viruses reactivate and cross into the brain after amyloid-related damage has already begun, said Keith Fargo, PhD, director of scientific programs and outreach at the Alzheimer’s Association. But the data in this paper are strong enough to give real credence, for the first time, to the idea that Alzheimer’s disease may have an infective component.
“This paper, which is quite dense, presents an idea we have seen before, but which has been mostly dismissed,” Dr. Fargo said in an interview. “For the first time, a world-class group of researchers have completed a landmark paper packed with evidence. It’s not definitive evidence yet, but it will certainly bring that hypothesis into the mainstream in a way it has not been before. The Alzheimer’s research world will sit up and take notice.”
The viruses were present in about 20% of AD brain samples taken from four separate brain banks, but not in control samples or in samples from patients with other neurodegenerative diseases. The commonality suggests that the association is real, and something unique to Alzheimer’s, said Sam Gandy, MD, PhD, one of the paper’s senior authors, and a professor of neurology at Mount Sinai Medical Center, New York.
Joel T. Dudley, PhD, director of the Mount Sinai Institute for Next Generation Healthcare, was the other senior author.
“It seems obvious to us that the AD brains around this country are accumulating the genomes of this particular pair of viruses,” Dr. Gandy said in an interview. “For whatever reason, these people were accumulating the genomes of an infectious agent which crossed the blood-brain barrier, went into the brain, and was present there when they were dying of AD. It was not a remote relationship, such as we would see with serology. This was there when they were dying, and it’s hard to imagine it was doing anything good.”
HHV6 causes a primary illness – roseola – when it first enters the body, usually in early childhood. It then enters a life-long latency, but can reactivate in adulthood, according to the HHV-6 Foundation.
“Reactivation can occur in the brain, lungs, heart, kidney, and gastrointestinal tract, especially in patients with immune deficiencies and transplant patients. In some cases, HHV-6 reactivation in the brain tissue can cause cognitive dysfunction, permanent disability, and death.”
The Neuron paper describes several separate investigations that led the team to conclude that HHV-6a and HHV-7 may be implicated in AD pathogenesis.
Dr. Gandy, Dr. Dudley, and their team were not looking for potentially infective agents when they started down this road 5 years ago. Instead, they wanted to see how genes and gene networks change as patients progress from preclinical Alzheimer’s to Alzheimer’s dementia, in the hope of finding novel drug targets.
“This was a surprise result. We were looking for genes differentially expressed as AD progressed. Instead, we found gene expression changes associated with viral infections.”
A transcriptome analysis pointed to microRNA-155, a molecule that helps control viral infections. This lead the team to look for viral RNA in 643 brain samples from the Mount Sinai Brain Bank. “What we found was that HHV-6a and HHV-7 appeared to be driving these changes,” Dr. Gandy said.
HHV-6a interacted with some of the most well-known AD risk genes, Dr. Gandy said.
“The story is full of tantalizing, yet not quite definitive pieces. Presenilin 1 is the most common cause of genetic forms of AD. There are about two dozen genes associated with late-onset sporadic AD. As we scrutinized the computational analysis of the data, whom should we find lurking there among the genes regulated by HHV-6a and HHV-7 but several of our old gene friends from conventional AD genetics and genome-wide association studies: PSEN1, BIN1, PICALM, among others, all of which are linked to causing AD.”
They validated the results from the Mount Sinai Brain Bank in three other data sets: the Religious Orders Study (300 samples from AD patients and healthy controls) the Rush Memory and Aging Project (298 samples from AD patients and healthy controls), and a collection of temporal cortex studies from the Mayo Clinic (278 samples from patients with AD, pathological aging, or progressive supranuclear palsy, and healthy controls).
Again, they saw HHV-6a and HHV-7 in the AD samples, but not in the normal controls or those with pathological aging. Compared with the AD samples, HHV-7 was present in the progressive supranuclear palsy samples, but HHV-6a was reduced.
Whole-exome sequencing found HHV-6a DNA integrated into host DNA. “This may indicate that the HHV-6a DNA that we find as more abundant in AD reflects HHV-6A that has undergone reactivation from a chromosomally integrated form, although we have not evaluated this directly,” Dr. Readhead and his co-investigators wrote in the paper.
Dr. Gandy said that the presence of the two viruses correlated directly with the patients’ Clinical Dementia Rating scale score, neuritic plaque density across multiple regions, and Braak stage, a measure of neurofibrillary tangles.
Another investigation looked at the fractions of the four major brain cells (neurons, astrocytes, microglia, and endothelial cells) and their relationship to viral RNA. HHV-6a was associated with decreases in the neuronal content of fractions from multiple brain regions, and in all four datasets.
Dr. Haure-Mirande and the team also studied a mouse model lacking the virus-suppressing microRNA-155 molecule and crossed this with one of the most commonly used AD research strains that overexpresses human amyloid precursor protein and develops brain amyloidosis. At 4 months, these mice had larger, more frequent amyloid plaques than the standard amyloidosis mice. Cortical RNA sequencing revealed overlap between upregulated genes in the microRNA-155 knockout mice and the HHV-6a–upregulated genes in human brains.
“These findings support the view of microRNA-155 as a regulator of complex anti- and pro-viral actions, offer a mechanism linking viral activity with AD pathology, and support the hypothesis that viral activity contributes to AD,” the investigators wrote.
As Dr. Gandy said, while not definitive, the studies are tantalizing and lay a solid framework for further investigation. He is confident enough about the association to view HHV as a potential therapeutic target for AD.
“The first step is to find a way to detect the viruses in people. We do have our first antibody to recognize one of the viral proteins, so we’re about to test that on blood serum, blood cells, and spinal fluid, and we will also look for viral DNA in the blood cells. Potentially – way down the road – we might be able to conduct a trial using antivirals,” to see if treatment could slow, or prevent, Alzheimer’s progression.
“These are nice, discrete, testable hypotheses, which makes them attractive,” Dr. Gandy said, “but the truth could be different and is almost certainly a lot messier.”
Dr. Gandy has received research funding from Baxter and Amicus Therapeutics, and personal remuneration from Pfizer and DiaGenic.
SOURCE: Readhead B et al. Neuron. 2018 June 21. doi: 10.1016/j.neuron.2018.05.023.
Two nearly ubiquitous herpes viruses are abundant in the brains of people with Alzheimer’s disease and appear to integrate themselves into the patient’s own genome, where the viruses play havoc with genes involved in Alzheimer’s pathogenesis, among other things, a new study reports.
The genomic analysis of hundreds of Alzheimer’s disease (AD) brain samples found human herpesvirus 6a and 7 (HHV-6a, HHV-7) in the entorhinal cortex and the hippocampus, the initial sites of beta-amyloid overexpression in the disease, first authors Benjamin Readhead, MBBS, Jean-Vianney Haure-Mirande, PhD, and colleagues reported June 21 in Neuron.
The viruses appear to interact with genes implicated in the risk for AD and for regulation and processing of the amyloid precursor protein, including presenilin-1 (PSEN1), BACE1, BIN1, PICALM, and several others. Their presence was directly related to the donors’ Clinical Dementia Rating score, and a mouse model suggests a potential pathway linking HHV infection and brain amyloidosis through a microRNA that’s been previously linked to AD.
It’s impossible to say whether HHV-6a and HHV-7 infections, which occur in nearly 100% of small children, trigger late-life amyloid pathology or whether the viruses reactivate and cross into the brain after amyloid-related damage has already begun, said Keith Fargo, PhD, director of scientific programs and outreach at the Alzheimer’s Association. But the data in this paper are strong enough to give real credence, for the first time, to the idea that Alzheimer’s disease may have an infective component.
“This paper, which is quite dense, presents an idea we have seen before, but which has been mostly dismissed,” Dr. Fargo said in an interview. “For the first time, a world-class group of researchers have completed a landmark paper packed with evidence. It’s not definitive evidence yet, but it will certainly bring that hypothesis into the mainstream in a way it has not been before. The Alzheimer’s research world will sit up and take notice.”
The viruses were present in about 20% of AD brain samples taken from four separate brain banks, but not in control samples or in samples from patients with other neurodegenerative diseases. The commonality suggests that the association is real, and something unique to Alzheimer’s, said Sam Gandy, MD, PhD, one of the paper’s senior authors, and a professor of neurology at Mount Sinai Medical Center, New York.
Joel T. Dudley, PhD, director of the Mount Sinai Institute for Next Generation Healthcare, was the other senior author.
“It seems obvious to us that the AD brains around this country are accumulating the genomes of this particular pair of viruses,” Dr. Gandy said in an interview. “For whatever reason, these people were accumulating the genomes of an infectious agent which crossed the blood-brain barrier, went into the brain, and was present there when they were dying of AD. It was not a remote relationship, such as we would see with serology. This was there when they were dying, and it’s hard to imagine it was doing anything good.”
HHV6 causes a primary illness – roseola – when it first enters the body, usually in early childhood. It then enters a life-long latency, but can reactivate in adulthood, according to the HHV-6 Foundation.
“Reactivation can occur in the brain, lungs, heart, kidney, and gastrointestinal tract, especially in patients with immune deficiencies and transplant patients. In some cases, HHV-6 reactivation in the brain tissue can cause cognitive dysfunction, permanent disability, and death.”
The Neuron paper describes several separate investigations that led the team to conclude that HHV-6a and HHV-7 may be implicated in AD pathogenesis.
Dr. Gandy, Dr. Dudley, and their team were not looking for potentially infective agents when they started down this road 5 years ago. Instead, they wanted to see how genes and gene networks change as patients progress from preclinical Alzheimer’s to Alzheimer’s dementia, in the hope of finding novel drug targets.
“This was a surprise result. We were looking for genes differentially expressed as AD progressed. Instead, we found gene expression changes associated with viral infections.”
A transcriptome analysis pointed to microRNA-155, a molecule that helps control viral infections. This lead the team to look for viral RNA in 643 brain samples from the Mount Sinai Brain Bank. “What we found was that HHV-6a and HHV-7 appeared to be driving these changes,” Dr. Gandy said.
HHV-6a interacted with some of the most well-known AD risk genes, Dr. Gandy said.
“The story is full of tantalizing, yet not quite definitive pieces. Presenilin 1 is the most common cause of genetic forms of AD. There are about two dozen genes associated with late-onset sporadic AD. As we scrutinized the computational analysis of the data, whom should we find lurking there among the genes regulated by HHV-6a and HHV-7 but several of our old gene friends from conventional AD genetics and genome-wide association studies: PSEN1, BIN1, PICALM, among others, all of which are linked to causing AD.”
They validated the results from the Mount Sinai Brain Bank in three other data sets: the Religious Orders Study (300 samples from AD patients and healthy controls) the Rush Memory and Aging Project (298 samples from AD patients and healthy controls), and a collection of temporal cortex studies from the Mayo Clinic (278 samples from patients with AD, pathological aging, or progressive supranuclear palsy, and healthy controls).
Again, they saw HHV-6a and HHV-7 in the AD samples, but not in the normal controls or those with pathological aging. Compared with the AD samples, HHV-7 was present in the progressive supranuclear palsy samples, but HHV-6a was reduced.
Whole-exome sequencing found HHV-6a DNA integrated into host DNA. “This may indicate that the HHV-6a DNA that we find as more abundant in AD reflects HHV-6A that has undergone reactivation from a chromosomally integrated form, although we have not evaluated this directly,” Dr. Readhead and his co-investigators wrote in the paper.
Dr. Gandy said that the presence of the two viruses correlated directly with the patients’ Clinical Dementia Rating scale score, neuritic plaque density across multiple regions, and Braak stage, a measure of neurofibrillary tangles.
Another investigation looked at the fractions of the four major brain cells (neurons, astrocytes, microglia, and endothelial cells) and their relationship to viral RNA. HHV-6a was associated with decreases in the neuronal content of fractions from multiple brain regions, and in all four datasets.
Dr. Haure-Mirande and the team also studied a mouse model lacking the virus-suppressing microRNA-155 molecule and crossed this with one of the most commonly used AD research strains that overexpresses human amyloid precursor protein and develops brain amyloidosis. At 4 months, these mice had larger, more frequent amyloid plaques than the standard amyloidosis mice. Cortical RNA sequencing revealed overlap between upregulated genes in the microRNA-155 knockout mice and the HHV-6a–upregulated genes in human brains.
“These findings support the view of microRNA-155 as a regulator of complex anti- and pro-viral actions, offer a mechanism linking viral activity with AD pathology, and support the hypothesis that viral activity contributes to AD,” the investigators wrote.
As Dr. Gandy said, while not definitive, the studies are tantalizing and lay a solid framework for further investigation. He is confident enough about the association to view HHV as a potential therapeutic target for AD.
“The first step is to find a way to detect the viruses in people. We do have our first antibody to recognize one of the viral proteins, so we’re about to test that on blood serum, blood cells, and spinal fluid, and we will also look for viral DNA in the blood cells. Potentially – way down the road – we might be able to conduct a trial using antivirals,” to see if treatment could slow, or prevent, Alzheimer’s progression.
“These are nice, discrete, testable hypotheses, which makes them attractive,” Dr. Gandy said, “but the truth could be different and is almost certainly a lot messier.”
Dr. Gandy has received research funding from Baxter and Amicus Therapeutics, and personal remuneration from Pfizer and DiaGenic.
SOURCE: Readhead B et al. Neuron. 2018 June 21. doi: 10.1016/j.neuron.2018.05.023.
FROM NEURON
Mother Knows Best
About six months ago, an 8-year-old girl developed an asymptomatic rash near her ear. Her mother suspects it is psoriasis, which runs heavily in the family—but their primary care provider favors a fungal diagnosis. He prescribes a succession of topical and oral antifungal medications (including nystatin and terbinafine), which yield no discernable improvement. At this point, referral to dermatology is made.
The child’s mother denies any history of recent infections (eg, strep throat) on her daughter’s behalf. Furthermore, there are no reports of pain associated with the rash or elsewhere.
EXAMINATION
The rash, which is confined to the external right ear, is composed of uniformly smooth white scale on a faintly salmon base. The entire lesion measures about 3 cm at its widest point, and the margins are arciform and well-defined.
No such lesions are seen elsewhere, but tiny pits can be seen on one fingernail.
What is the diagnosis?
DISCUSSION
A punch biopsy could have confirmed the diagnosis, but with the family history, classic appearance, and lack of response to antifungal medication, there was little doubt that this was a case of psoriasis. This autoimmune disease affects nearly 3% of the white population in this country and has a genetic component about 30% of the time.
In psoriasis, keratinocytes matriculate upward from the basal layer to the skin surface at four times the normal rate—so quickly that they have no chance to lose their nuclei (as they normally would). They then pile up, creating plaques of micaceous white scale on a salmon-pink base. Histologically, the smoothly undulating dermoepidermal junction is jammed together, producing fused ridges with clumps of neutrophils on their tips.
While it favors extensor surfaces of extremities, psoriasis can show up anywhere on the body—on the genitals, mouth, and in the nails, where it can cause pits, dystrophy, discoloration, onycholysis, and onychorrhexis.
Unfortunately, this is probably just the beginning of this child’s psoriasis. The good news is that we’re in a golden age of psoriasis treatment, with more drugs than ever to choose from and even more in development. For this patient, we used a keratolytic agent (urea lotion) to thin out the surface scale, in order to allow a class 4 steroid cream to reach the pink inflammatory portion. Within a month, most of this patch had cleared, though we can be fairly sure it and others like it will be back. Education and ongoing follow-up will be needed, in case she is among the 20% to 25% of patients who will develop psoriatic arthropathy, a crippling form of arthritis.
It is certainly possible to develop a fungal infection on or in an ear, but for that to happen, there has to be a source (eg, animal, person, soil). Moreover, the scale would look entirely different, with clearing centers and advancing margins. The likely truth is that this was called “fungal” for lack of any other suspects.
TAKE-HOME LEARNING POINTS
- White scale on a salmon-pink base typifies psoriasis vulgaris, a very common diagnosis that is often mistaken for fungal infection; biopsy can be extremely helpful in establishing or ruling out this diagnosis.
- Psoriasis has a genetic basis, with many gene loci identified to date, but only about 30% of affected patients can attest to a family history.
- In addition to having unsightly, often itchy lesions, psoriasis patients are also at risk for psoriatic arthropathy, a potentially crippling condition.
- The best news is that we have many drugs with which to treat this disease, including a whole family of drugs termed “the biologics,” which directly (and successfully!) address the disease.
About six months ago, an 8-year-old girl developed an asymptomatic rash near her ear. Her mother suspects it is psoriasis, which runs heavily in the family—but their primary care provider favors a fungal diagnosis. He prescribes a succession of topical and oral antifungal medications (including nystatin and terbinafine), which yield no discernable improvement. At this point, referral to dermatology is made.
The child’s mother denies any history of recent infections (eg, strep throat) on her daughter’s behalf. Furthermore, there are no reports of pain associated with the rash or elsewhere.
EXAMINATION
The rash, which is confined to the external right ear, is composed of uniformly smooth white scale on a faintly salmon base. The entire lesion measures about 3 cm at its widest point, and the margins are arciform and well-defined.
No such lesions are seen elsewhere, but tiny pits can be seen on one fingernail.
What is the diagnosis?
DISCUSSION
A punch biopsy could have confirmed the diagnosis, but with the family history, classic appearance, and lack of response to antifungal medication, there was little doubt that this was a case of psoriasis. This autoimmune disease affects nearly 3% of the white population in this country and has a genetic component about 30% of the time.
In psoriasis, keratinocytes matriculate upward from the basal layer to the skin surface at four times the normal rate—so quickly that they have no chance to lose their nuclei (as they normally would). They then pile up, creating plaques of micaceous white scale on a salmon-pink base. Histologically, the smoothly undulating dermoepidermal junction is jammed together, producing fused ridges with clumps of neutrophils on their tips.
While it favors extensor surfaces of extremities, psoriasis can show up anywhere on the body—on the genitals, mouth, and in the nails, where it can cause pits, dystrophy, discoloration, onycholysis, and onychorrhexis.
Unfortunately, this is probably just the beginning of this child’s psoriasis. The good news is that we’re in a golden age of psoriasis treatment, with more drugs than ever to choose from and even more in development. For this patient, we used a keratolytic agent (urea lotion) to thin out the surface scale, in order to allow a class 4 steroid cream to reach the pink inflammatory portion. Within a month, most of this patch had cleared, though we can be fairly sure it and others like it will be back. Education and ongoing follow-up will be needed, in case she is among the 20% to 25% of patients who will develop psoriatic arthropathy, a crippling form of arthritis.
It is certainly possible to develop a fungal infection on or in an ear, but for that to happen, there has to be a source (eg, animal, person, soil). Moreover, the scale would look entirely different, with clearing centers and advancing margins. The likely truth is that this was called “fungal” for lack of any other suspects.
TAKE-HOME LEARNING POINTS
- White scale on a salmon-pink base typifies psoriasis vulgaris, a very common diagnosis that is often mistaken for fungal infection; biopsy can be extremely helpful in establishing or ruling out this diagnosis.
- Psoriasis has a genetic basis, with many gene loci identified to date, but only about 30% of affected patients can attest to a family history.
- In addition to having unsightly, often itchy lesions, psoriasis patients are also at risk for psoriatic arthropathy, a potentially crippling condition.
- The best news is that we have many drugs with which to treat this disease, including a whole family of drugs termed “the biologics,” which directly (and successfully!) address the disease.
About six months ago, an 8-year-old girl developed an asymptomatic rash near her ear. Her mother suspects it is psoriasis, which runs heavily in the family—but their primary care provider favors a fungal diagnosis. He prescribes a succession of topical and oral antifungal medications (including nystatin and terbinafine), which yield no discernable improvement. At this point, referral to dermatology is made.
The child’s mother denies any history of recent infections (eg, strep throat) on her daughter’s behalf. Furthermore, there are no reports of pain associated with the rash or elsewhere.
EXAMINATION
The rash, which is confined to the external right ear, is composed of uniformly smooth white scale on a faintly salmon base. The entire lesion measures about 3 cm at its widest point, and the margins are arciform and well-defined.
No such lesions are seen elsewhere, but tiny pits can be seen on one fingernail.
What is the diagnosis?
DISCUSSION
A punch biopsy could have confirmed the diagnosis, but with the family history, classic appearance, and lack of response to antifungal medication, there was little doubt that this was a case of psoriasis. This autoimmune disease affects nearly 3% of the white population in this country and has a genetic component about 30% of the time.
In psoriasis, keratinocytes matriculate upward from the basal layer to the skin surface at four times the normal rate—so quickly that they have no chance to lose their nuclei (as they normally would). They then pile up, creating plaques of micaceous white scale on a salmon-pink base. Histologically, the smoothly undulating dermoepidermal junction is jammed together, producing fused ridges with clumps of neutrophils on their tips.
While it favors extensor surfaces of extremities, psoriasis can show up anywhere on the body—on the genitals, mouth, and in the nails, where it can cause pits, dystrophy, discoloration, onycholysis, and onychorrhexis.
Unfortunately, this is probably just the beginning of this child’s psoriasis. The good news is that we’re in a golden age of psoriasis treatment, with more drugs than ever to choose from and even more in development. For this patient, we used a keratolytic agent (urea lotion) to thin out the surface scale, in order to allow a class 4 steroid cream to reach the pink inflammatory portion. Within a month, most of this patch had cleared, though we can be fairly sure it and others like it will be back. Education and ongoing follow-up will be needed, in case she is among the 20% to 25% of patients who will develop psoriatic arthropathy, a crippling form of arthritis.
It is certainly possible to develop a fungal infection on or in an ear, but for that to happen, there has to be a source (eg, animal, person, soil). Moreover, the scale would look entirely different, with clearing centers and advancing margins. The likely truth is that this was called “fungal” for lack of any other suspects.
TAKE-HOME LEARNING POINTS
- White scale on a salmon-pink base typifies psoriasis vulgaris, a very common diagnosis that is often mistaken for fungal infection; biopsy can be extremely helpful in establishing or ruling out this diagnosis.
- Psoriasis has a genetic basis, with many gene loci identified to date, but only about 30% of affected patients can attest to a family history.
- In addition to having unsightly, often itchy lesions, psoriasis patients are also at risk for psoriatic arthropathy, a potentially crippling condition.
- The best news is that we have many drugs with which to treat this disease, including a whole family of drugs termed “the biologics,” which directly (and successfully!) address the disease.
Don’t Miss Practice Management Tips for Novice and Seasoned Surgeons
Young vascular surgeons looking to make their marks and balance their lives, as well as more experienced surgeons seeking tips for more effective practice and career management, should consider the session led by Jeffrey Siracuse, MD, of Boston Medical Center, and Courtney Warner, MD, of Albany Medical College, Saratoga Springs, N.Y.
“This will be a great and informative session that, although geared toward young surgeons, will be highly useful for surgeons of all experience levels,” Dr. Siracuse said of the session.
“Topics include building a successful academic practice, building a successful private practice, how to work with other specialties, how to negotiate a contract, how to improve one’s current job, and more on the business side of medicine,” said Dr. Siracuse. The discussions will be followed by a Q&A panel.
The first job after a fellowship is often the first “real job” of any type that new surgeons have had, Dr. Siracuse said. Medical school offers many things, but young surgeons may be underprepared for how to negotiate for one’s first surgical position and how to set oneself up for success, he explained. That said, the keys for success are significantly different for surgeons entering an academic setting or private practice, he noted.
The session kicks off with presenters addressing both types of practice.
Faisal Aziz, MD, of Penn State Hershey College of Medicine, Hershey, addresses the “Top 10 Roadblocks to a Successful Academic Practice,” and Scott Berman, MD, of Carondelet Medical Group in Tucson, Ariz., takes on the “Top 10 Roadblocks to a Successful Private Practice.”
Some subjects likely to prompt lively discussion among seasoned veteran surgeons as well as novices include how to effectively negotiate and renegotiate contracts. The contracts presentation, “Top 10 Tips on Negotiating Contracts and Other Things I Learned in Business School,” is scheduled to be given by Bruce Perler, MD, of Johns Hopkins University in Baltimore, Md.
In addition, surgeons at all levels of experience can benefit from tips on how to work with individuals in other specialties, especially if one is competing with them for patients and cases, Dr. Siracuse said. Brandon Propper, MD, of San Antonio Military Medical Center, Texas, steps up to the plate with his “Top 10 Ways to Work With Other Specialties.”
The Practice Management Tips and Tricks for Young Vascular Surgeons session is recommended by the Community Practice Committee and the Young Surgeons Committee.
Friday, June 22
1:30 – 3:00 p.m.
HCC, Room 311
C5: Practice Management Tips and Tricks for Young Vascular Surgeons
Young vascular surgeons looking to make their marks and balance their lives, as well as more experienced surgeons seeking tips for more effective practice and career management, should consider the session led by Jeffrey Siracuse, MD, of Boston Medical Center, and Courtney Warner, MD, of Albany Medical College, Saratoga Springs, N.Y.
“This will be a great and informative session that, although geared toward young surgeons, will be highly useful for surgeons of all experience levels,” Dr. Siracuse said of the session.
“Topics include building a successful academic practice, building a successful private practice, how to work with other specialties, how to negotiate a contract, how to improve one’s current job, and more on the business side of medicine,” said Dr. Siracuse. The discussions will be followed by a Q&A panel.
The first job after a fellowship is often the first “real job” of any type that new surgeons have had, Dr. Siracuse said. Medical school offers many things, but young surgeons may be underprepared for how to negotiate for one’s first surgical position and how to set oneself up for success, he explained. That said, the keys for success are significantly different for surgeons entering an academic setting or private practice, he noted.
The session kicks off with presenters addressing both types of practice.
Faisal Aziz, MD, of Penn State Hershey College of Medicine, Hershey, addresses the “Top 10 Roadblocks to a Successful Academic Practice,” and Scott Berman, MD, of Carondelet Medical Group in Tucson, Ariz., takes on the “Top 10 Roadblocks to a Successful Private Practice.”
Some subjects likely to prompt lively discussion among seasoned veteran surgeons as well as novices include how to effectively negotiate and renegotiate contracts. The contracts presentation, “Top 10 Tips on Negotiating Contracts and Other Things I Learned in Business School,” is scheduled to be given by Bruce Perler, MD, of Johns Hopkins University in Baltimore, Md.
In addition, surgeons at all levels of experience can benefit from tips on how to work with individuals in other specialties, especially if one is competing with them for patients and cases, Dr. Siracuse said. Brandon Propper, MD, of San Antonio Military Medical Center, Texas, steps up to the plate with his “Top 10 Ways to Work With Other Specialties.”
The Practice Management Tips and Tricks for Young Vascular Surgeons session is recommended by the Community Practice Committee and the Young Surgeons Committee.
Friday, June 22
1:30 – 3:00 p.m.
HCC, Room 311
C5: Practice Management Tips and Tricks for Young Vascular Surgeons
Young vascular surgeons looking to make their marks and balance their lives, as well as more experienced surgeons seeking tips for more effective practice and career management, should consider the session led by Jeffrey Siracuse, MD, of Boston Medical Center, and Courtney Warner, MD, of Albany Medical College, Saratoga Springs, N.Y.
“This will be a great and informative session that, although geared toward young surgeons, will be highly useful for surgeons of all experience levels,” Dr. Siracuse said of the session.
“Topics include building a successful academic practice, building a successful private practice, how to work with other specialties, how to negotiate a contract, how to improve one’s current job, and more on the business side of medicine,” said Dr. Siracuse. The discussions will be followed by a Q&A panel.
The first job after a fellowship is often the first “real job” of any type that new surgeons have had, Dr. Siracuse said. Medical school offers many things, but young surgeons may be underprepared for how to negotiate for one’s first surgical position and how to set oneself up for success, he explained. That said, the keys for success are significantly different for surgeons entering an academic setting or private practice, he noted.
The session kicks off with presenters addressing both types of practice.
Faisal Aziz, MD, of Penn State Hershey College of Medicine, Hershey, addresses the “Top 10 Roadblocks to a Successful Academic Practice,” and Scott Berman, MD, of Carondelet Medical Group in Tucson, Ariz., takes on the “Top 10 Roadblocks to a Successful Private Practice.”
Some subjects likely to prompt lively discussion among seasoned veteran surgeons as well as novices include how to effectively negotiate and renegotiate contracts. The contracts presentation, “Top 10 Tips on Negotiating Contracts and Other Things I Learned in Business School,” is scheduled to be given by Bruce Perler, MD, of Johns Hopkins University in Baltimore, Md.
In addition, surgeons at all levels of experience can benefit from tips on how to work with individuals in other specialties, especially if one is competing with them for patients and cases, Dr. Siracuse said. Brandon Propper, MD, of San Antonio Military Medical Center, Texas, steps up to the plate with his “Top 10 Ways to Work With Other Specialties.”
The Practice Management Tips and Tricks for Young Vascular Surgeons session is recommended by the Community Practice Committee and the Young Surgeons Committee.
Friday, June 22
1:30 – 3:00 p.m.
HCC, Room 311
C5: Practice Management Tips and Tricks for Young Vascular Surgeons
Mix and Mingle at Friday’s Closing Reception
Mark the closing of the Exhibit Hall by attending the Closing Reception, set for 4:30 to 5:30 p.m. Friday in the Auditorium on Level 2 of the Hynes Convention Center.
VAM attendees have one more chance to visit with vendors and check out innovations in devices and medications. Guests have another to meet with friends old and new, to relax, and to enjoy cocktails and hors d’oeuvres.
Tickets are required and are available at Registration.
Mark the closing of the Exhibit Hall by attending the Closing Reception, set for 4:30 to 5:30 p.m. Friday in the Auditorium on Level 2 of the Hynes Convention Center.
VAM attendees have one more chance to visit with vendors and check out innovations in devices and medications. Guests have another to meet with friends old and new, to relax, and to enjoy cocktails and hors d’oeuvres.
Tickets are required and are available at Registration.
Mark the closing of the Exhibit Hall by attending the Closing Reception, set for 4:30 to 5:30 p.m. Friday in the Auditorium on Level 2 of the Hynes Convention Center.
VAM attendees have one more chance to visit with vendors and check out innovations in devices and medications. Guests have another to meet with friends old and new, to relax, and to enjoy cocktails and hors d’oeuvres.
Tickets are required and are available at Registration.
Advanced Practice Providers Vital to Vascular Team
The team approach has changed the entire field of medicine in the past 10-20 years and, in fact, is critical to optimal patient outcomes. That’s according to Anil Hingorani, MD, who will co-moderate a special forum Friday, “Improving Clinical Metrics With the Utilization of Advanced Practice Providers.”
It will be held from 1:30 to 3 p.m. in Ballroom A/B.
The team approach is front and center at this year’s Vascular Annual Meeting, which carries the theme: “Home of the Vascular Team – Partners in Patient Care.”
“Our vascular disease patients can be quite complex,” said Dr. Hingorani. “We will highlight that to take care of these complexities we need a team approach, and our team members can help tremendously.” This is true across the setting spectrum, be it rural, urban, suburban.
“Some NPs and PAs run our service. They help coordinate pre-op evaluations, post-op management, take care of research protocols, billing, and other office responsibilities,” he said.
He pointed out he is not a specialist in diabetes, but that his NP has a special interest and passion for the topic. The work she does for their diabetic patients “helps MY patients and helps MY procedures have better outcomes.”
PAs and NPs also help run research projects and are instrumental in working with fellows rotating through. With their work in what Dr. Hingorani referred to as the “three pillars” – clinical work, teaching, and research – they are tremendously important to the vascular team.
Advanced care providers also help improve outcomes, he said, when pay for performance and quantitating outcomes is becoming a standard part of health care. Admissions, discharges, surgical site infections, diabetes, follow-up all are important for patient care, and tracking all the details is vital to outcomes. It will be addressed in the forum, Dr. Hingorani said.
“Medicine is a specialty that hasn’t really caught on to MACRA, MIPS, and what pay for performance really entails,” he said. “Many are still figuring out, ‘What changes do I need to make to make this work for my patients and me? Where does my practice fit in?’ We’re going to have to keep working on that.”
Speakers will be primarily nurse practitioners and physician assistants. “We didn’t want surgeons telling PAs and NPs what they should be doing. It needs to be the PAs and NPs doing the speaking, focusing on issues important to them.”
Dr. Hingorani believes that the Vascular Annual Meeting is the first to stress the team approach theme. “I think it’s an important step and others will follow suit,” he said. “These ideas are resonating. They’re important and will be the way forward.
“I think we’ll be breaking new ground and will ripple across the societies.”
Besides a panel discussion at the end, forum topics include:
- Improving Metrics in Clinical Practice: The Value of APPs to a Vascular Practice
- There’s an APP for That: Workforce and Community Practice Experience
- National and International Trends in the Use of APPs, PAs in Surgery and Outcome Data
- Improving Metrics via Team-Based Care: The Wake Forest Baptist Health Experience
- Influence of APPs - MIPS and “Throughput” of Patients, Value/Quality/Financial Benefit and APPs
- Funny You Should Ask: What Advanced Practice Providers Bring to the Table
- How Advanced Practice Clinicians Can Add Value to Your Practice
- Driving Outcomes: University of Maryland Advanced Practice Providers Target Preventable Complications, Length of Stay, and Readmissions Univers LT Std
The team approach has changed the entire field of medicine in the past 10-20 years and, in fact, is critical to optimal patient outcomes. That’s according to Anil Hingorani, MD, who will co-moderate a special forum Friday, “Improving Clinical Metrics With the Utilization of Advanced Practice Providers.”
It will be held from 1:30 to 3 p.m. in Ballroom A/B.
The team approach is front and center at this year’s Vascular Annual Meeting, which carries the theme: “Home of the Vascular Team – Partners in Patient Care.”
“Our vascular disease patients can be quite complex,” said Dr. Hingorani. “We will highlight that to take care of these complexities we need a team approach, and our team members can help tremendously.” This is true across the setting spectrum, be it rural, urban, suburban.
“Some NPs and PAs run our service. They help coordinate pre-op evaluations, post-op management, take care of research protocols, billing, and other office responsibilities,” he said.
He pointed out he is not a specialist in diabetes, but that his NP has a special interest and passion for the topic. The work she does for their diabetic patients “helps MY patients and helps MY procedures have better outcomes.”
PAs and NPs also help run research projects and are instrumental in working with fellows rotating through. With their work in what Dr. Hingorani referred to as the “three pillars” – clinical work, teaching, and research – they are tremendously important to the vascular team.
Advanced care providers also help improve outcomes, he said, when pay for performance and quantitating outcomes is becoming a standard part of health care. Admissions, discharges, surgical site infections, diabetes, follow-up all are important for patient care, and tracking all the details is vital to outcomes. It will be addressed in the forum, Dr. Hingorani said.
“Medicine is a specialty that hasn’t really caught on to MACRA, MIPS, and what pay for performance really entails,” he said. “Many are still figuring out, ‘What changes do I need to make to make this work for my patients and me? Where does my practice fit in?’ We’re going to have to keep working on that.”
Speakers will be primarily nurse practitioners and physician assistants. “We didn’t want surgeons telling PAs and NPs what they should be doing. It needs to be the PAs and NPs doing the speaking, focusing on issues important to them.”
Dr. Hingorani believes that the Vascular Annual Meeting is the first to stress the team approach theme. “I think it’s an important step and others will follow suit,” he said. “These ideas are resonating. They’re important and will be the way forward.
“I think we’ll be breaking new ground and will ripple across the societies.”
Besides a panel discussion at the end, forum topics include:
- Improving Metrics in Clinical Practice: The Value of APPs to a Vascular Practice
- There’s an APP for That: Workforce and Community Practice Experience
- National and International Trends in the Use of APPs, PAs in Surgery and Outcome Data
- Improving Metrics via Team-Based Care: The Wake Forest Baptist Health Experience
- Influence of APPs - MIPS and “Throughput” of Patients, Value/Quality/Financial Benefit and APPs
- Funny You Should Ask: What Advanced Practice Providers Bring to the Table
- How Advanced Practice Clinicians Can Add Value to Your Practice
- Driving Outcomes: University of Maryland Advanced Practice Providers Target Preventable Complications, Length of Stay, and Readmissions Univers LT Std
The team approach has changed the entire field of medicine in the past 10-20 years and, in fact, is critical to optimal patient outcomes. That’s according to Anil Hingorani, MD, who will co-moderate a special forum Friday, “Improving Clinical Metrics With the Utilization of Advanced Practice Providers.”
It will be held from 1:30 to 3 p.m. in Ballroom A/B.
The team approach is front and center at this year’s Vascular Annual Meeting, which carries the theme: “Home of the Vascular Team – Partners in Patient Care.”
“Our vascular disease patients can be quite complex,” said Dr. Hingorani. “We will highlight that to take care of these complexities we need a team approach, and our team members can help tremendously.” This is true across the setting spectrum, be it rural, urban, suburban.
“Some NPs and PAs run our service. They help coordinate pre-op evaluations, post-op management, take care of research protocols, billing, and other office responsibilities,” he said.
He pointed out he is not a specialist in diabetes, but that his NP has a special interest and passion for the topic. The work she does for their diabetic patients “helps MY patients and helps MY procedures have better outcomes.”
PAs and NPs also help run research projects and are instrumental in working with fellows rotating through. With their work in what Dr. Hingorani referred to as the “three pillars” – clinical work, teaching, and research – they are tremendously important to the vascular team.
Advanced care providers also help improve outcomes, he said, when pay for performance and quantitating outcomes is becoming a standard part of health care. Admissions, discharges, surgical site infections, diabetes, follow-up all are important for patient care, and tracking all the details is vital to outcomes. It will be addressed in the forum, Dr. Hingorani said.
“Medicine is a specialty that hasn’t really caught on to MACRA, MIPS, and what pay for performance really entails,” he said. “Many are still figuring out, ‘What changes do I need to make to make this work for my patients and me? Where does my practice fit in?’ We’re going to have to keep working on that.”
Speakers will be primarily nurse practitioners and physician assistants. “We didn’t want surgeons telling PAs and NPs what they should be doing. It needs to be the PAs and NPs doing the speaking, focusing on issues important to them.”
Dr. Hingorani believes that the Vascular Annual Meeting is the first to stress the team approach theme. “I think it’s an important step and others will follow suit,” he said. “These ideas are resonating. They’re important and will be the way forward.
“I think we’ll be breaking new ground and will ripple across the societies.”
Besides a panel discussion at the end, forum topics include:
- Improving Metrics in Clinical Practice: The Value of APPs to a Vascular Practice
- There’s an APP for That: Workforce and Community Practice Experience
- National and International Trends in the Use of APPs, PAs in Surgery and Outcome Data
- Improving Metrics via Team-Based Care: The Wake Forest Baptist Health Experience
- Influence of APPs - MIPS and “Throughput” of Patients, Value/Quality/Financial Benefit and APPs
- Funny You Should Ask: What Advanced Practice Providers Bring to the Table
- How Advanced Practice Clinicians Can Add Value to Your Practice
- Driving Outcomes: University of Maryland Advanced Practice Providers Target Preventable Complications, Length of Stay, and Readmissions Univers LT Std
Dialectical behavior therapy reduces suicide attempts in adolescents
A form of behavioral therapy that focuses on enhancing emotion regulation, distress tolerance, and improving quality of life has shown promise in reducing self-harm and suicide attempts in adolescents, according to new research.
In a paper published in JAMA Psychiatry, researchers reported the outcomes of a randomized trial of dialectical behavior therapy (DBT) versus individual and group supportive therapy in 173 adolescents with a history of suicide attempts.
DBT, developed by Marsha Linehan, PhD, as a team-based intervention for chronically suicidal patients with borderline personality disorder, is aimed at getting patients to focus on changing their behaviors so that they are able to meet their long-term goals. The use of DBT with adults has been tied to low dropout rates, and has been effective at reducing suicide attempts and self-harm.
In the study, the DBT consisted of weekly individual psychotherapy, multifamily group skills training, youth and parent telephone coaching, and a weekly therapist team consultation. The control group took part in individual sessions, group therapy, as-needed parent sessions, and a weekly therapist team consultation.
Researchers saw a 70% lower rate of suicide attempts, 68% lower rate of nonsuicidal self-injury, and 67% lower rate of self-harm in the DBT group, compared with the control group at the end of the 6-month treatment course. However, at 12 months, the differences between the two groups were no longer statistically significant.
“This is the first adolescent RCT [randomized, controlled trial] to our knowledge to demonstrate that DBT is effective at decreasing suicide attempts,” Elizabeth A. McCauley, PhD, of the Seattle Children’s Research Institute, and her coauthors.
At 12 months, those figures were 51.2% and 32.2% respectively.
Significantly, more participants in the DBT group completed the treatment, compared with those in individual and group supportive therapy (75.6% vs. 55.2%), although this did not appear to be responsible for the difference in outcomes.
“Although results of pattern-mixture models found no evidence of an informative attrition mechanism, we cannot rule out the possibility that differential treatment exposure is a mechanism that leads to the DBT outcomes,” the authors wrote. “Stronger DBT treatment retention is, however, an important finding given prior research that found difficulties with treatment engagement, and adherence among suicidal and self-harming youths.”
Parents were involved in both treatments, but “DBT included greater family involvement,” Dr. McCauley and her coauthors wrote. “This difference may have contributed to both greater retention and treatment effects, particularly because stronger family components are associated with treatment benefits for adolescent self-harm.”
The authors said the fact that both groups improved after 12 months provided support for the individual and group supportive therapy in these patients.
“Our findings add to data supporting other promising treatment approaches, including cognitive-behavioral therapy, mentalization-based therapy, and family-based treatments,” they concluded
The study was supported by the National Institutes of Mental Health. Eight authors declared grant support from NIMH, and two authors declared other funding unrelated to the study.
SOURCE: McCauley EA et al. JAMA Psychiatry. 2018 Jun 20. doi:10.1001/jamapsychiatry.2018.1109.
A form of behavioral therapy that focuses on enhancing emotion regulation, distress tolerance, and improving quality of life has shown promise in reducing self-harm and suicide attempts in adolescents, according to new research.
In a paper published in JAMA Psychiatry, researchers reported the outcomes of a randomized trial of dialectical behavior therapy (DBT) versus individual and group supportive therapy in 173 adolescents with a history of suicide attempts.
DBT, developed by Marsha Linehan, PhD, as a team-based intervention for chronically suicidal patients with borderline personality disorder, is aimed at getting patients to focus on changing their behaviors so that they are able to meet their long-term goals. The use of DBT with adults has been tied to low dropout rates, and has been effective at reducing suicide attempts and self-harm.
In the study, the DBT consisted of weekly individual psychotherapy, multifamily group skills training, youth and parent telephone coaching, and a weekly therapist team consultation. The control group took part in individual sessions, group therapy, as-needed parent sessions, and a weekly therapist team consultation.
Researchers saw a 70% lower rate of suicide attempts, 68% lower rate of nonsuicidal self-injury, and 67% lower rate of self-harm in the DBT group, compared with the control group at the end of the 6-month treatment course. However, at 12 months, the differences between the two groups were no longer statistically significant.
“This is the first adolescent RCT [randomized, controlled trial] to our knowledge to demonstrate that DBT is effective at decreasing suicide attempts,” Elizabeth A. McCauley, PhD, of the Seattle Children’s Research Institute, and her coauthors.
At 12 months, those figures were 51.2% and 32.2% respectively.
Significantly, more participants in the DBT group completed the treatment, compared with those in individual and group supportive therapy (75.6% vs. 55.2%), although this did not appear to be responsible for the difference in outcomes.
“Although results of pattern-mixture models found no evidence of an informative attrition mechanism, we cannot rule out the possibility that differential treatment exposure is a mechanism that leads to the DBT outcomes,” the authors wrote. “Stronger DBT treatment retention is, however, an important finding given prior research that found difficulties with treatment engagement, and adherence among suicidal and self-harming youths.”
Parents were involved in both treatments, but “DBT included greater family involvement,” Dr. McCauley and her coauthors wrote. “This difference may have contributed to both greater retention and treatment effects, particularly because stronger family components are associated with treatment benefits for adolescent self-harm.”
The authors said the fact that both groups improved after 12 months provided support for the individual and group supportive therapy in these patients.
“Our findings add to data supporting other promising treatment approaches, including cognitive-behavioral therapy, mentalization-based therapy, and family-based treatments,” they concluded
The study was supported by the National Institutes of Mental Health. Eight authors declared grant support from NIMH, and two authors declared other funding unrelated to the study.
SOURCE: McCauley EA et al. JAMA Psychiatry. 2018 Jun 20. doi:10.1001/jamapsychiatry.2018.1109.
A form of behavioral therapy that focuses on enhancing emotion regulation, distress tolerance, and improving quality of life has shown promise in reducing self-harm and suicide attempts in adolescents, according to new research.
In a paper published in JAMA Psychiatry, researchers reported the outcomes of a randomized trial of dialectical behavior therapy (DBT) versus individual and group supportive therapy in 173 adolescents with a history of suicide attempts.
DBT, developed by Marsha Linehan, PhD, as a team-based intervention for chronically suicidal patients with borderline personality disorder, is aimed at getting patients to focus on changing their behaviors so that they are able to meet their long-term goals. The use of DBT with adults has been tied to low dropout rates, and has been effective at reducing suicide attempts and self-harm.
In the study, the DBT consisted of weekly individual psychotherapy, multifamily group skills training, youth and parent telephone coaching, and a weekly therapist team consultation. The control group took part in individual sessions, group therapy, as-needed parent sessions, and a weekly therapist team consultation.
Researchers saw a 70% lower rate of suicide attempts, 68% lower rate of nonsuicidal self-injury, and 67% lower rate of self-harm in the DBT group, compared with the control group at the end of the 6-month treatment course. However, at 12 months, the differences between the two groups were no longer statistically significant.
“This is the first adolescent RCT [randomized, controlled trial] to our knowledge to demonstrate that DBT is effective at decreasing suicide attempts,” Elizabeth A. McCauley, PhD, of the Seattle Children’s Research Institute, and her coauthors.
At 12 months, those figures were 51.2% and 32.2% respectively.
Significantly, more participants in the DBT group completed the treatment, compared with those in individual and group supportive therapy (75.6% vs. 55.2%), although this did not appear to be responsible for the difference in outcomes.
“Although results of pattern-mixture models found no evidence of an informative attrition mechanism, we cannot rule out the possibility that differential treatment exposure is a mechanism that leads to the DBT outcomes,” the authors wrote. “Stronger DBT treatment retention is, however, an important finding given prior research that found difficulties with treatment engagement, and adherence among suicidal and self-harming youths.”
Parents were involved in both treatments, but “DBT included greater family involvement,” Dr. McCauley and her coauthors wrote. “This difference may have contributed to both greater retention and treatment effects, particularly because stronger family components are associated with treatment benefits for adolescent self-harm.”
The authors said the fact that both groups improved after 12 months provided support for the individual and group supportive therapy in these patients.
“Our findings add to data supporting other promising treatment approaches, including cognitive-behavioral therapy, mentalization-based therapy, and family-based treatments,” they concluded
The study was supported by the National Institutes of Mental Health. Eight authors declared grant support from NIMH, and two authors declared other funding unrelated to the study.
SOURCE: McCauley EA et al. JAMA Psychiatry. 2018 Jun 20. doi:10.1001/jamapsychiatry.2018.1109.
FROM JAMA PSYCHIATRY
Key clinical point: Dialectical behavior therapy reduces suicide attempts and self-harm in adolescents.
Major finding: DBT showed a 70% reduction in suicide attempts, compared with controls.
Study details: A randomized, controlled study of 173 adolescents with a history of suicide attempts.
Disclosures: The study was supported by the National Institutes of Mental Health. Eight authors declared grant support from NIMH, and two authors declared other funding unrelated to the study.
Source: McCauley EA et al. JAMA Psychiatry. 2018 Jun 20. doi: 10.1001/jamapsychiatry.2018.1109.
Recurrence of a small gastric gastrointestinal stromal tumor with high mitotic index
Gastrointestinal stromal tumor (GIST) is the most common soft tissue sarcoma of the gastrointestinal tract, usually arising from the interstitial cells of Cajal or similar cells in the outer wall of the gastrointestinal tract.1,2 Most GISTs have an activating mutation in KIT or platelet-derived growth factor receptor alpha (PDGFRA). Tumor size, mitotic rate, and anatomic site are the most common pathological features used to risk stratify GIST tumors.3-10 It is important to note when using such risk calculators that preoperative imatinib before determining tumor characteristics (such as mitoses per 50 high-power fields [hpf]) often changes the relevant parameters so that the same risk calculations may not apply. Tumors with a mitotic rate ≤5 mitoses per 50 hpf and a size ≤5 cm in greatest dimension have a lower recurrence rate after resection than tumors with a mitotic rate >5 mitoses per 50 hpf and a size >10 cm, and larger tumors can have a recurrence rate of up to 86%.11,12 Findings from a large observational study have suggested that the prognosis of gastric GIST in Korea and Japan may be more favorable compared with that in Western countries.13
The primary treatment of a localized primary GIST is surgical excision, but a cure is limited by recurrence.14,15 Imatinib is useful in the treatment of metastatic or recurrent GIST, and adjuvant treatment with imatinib after surgery has been shown to improve progression-free and overall survival in some cases.3,16-18 Responses to adjuvant imatinib depend on tumor sensitivity to the drug and the risk of recurrence. Drug sensitivity is largely dependent on the presence of mutations in KIT or PDGFRA.3,18 Recurrence risk is highly dependent on tumor size, tumor site, tumor rupture, and mitotic index.1,3,5,6,8,9,18,19 Findings on the use of gene expression patterns to predict recurrence risk have also been reported.20-27 However, recurrence risk is poorly understood for categories in which there are few cases with known outcomes, such as very small gastric GIST with a high mitotic index. For example, few cases of gastric GIST have been reported with a tumor size ≤2 cm, a mitotic rate >5 mitoses per 50 hpf, and adequate clinical follow-up. In such cases, it is difficult to assess the risk of recurrence.6 We report here the long-term outcome of a patient with a 1.8 cm gastric GIST with a mitotic index of 36 mitoses per 50 hpf and a KIT exon 11 mutation.
Case presentation and summary
A 69-year-old man presented with periumbilical and epigastric pain of 6-month duration. His medical history was notable for hyperlipidemia, hypertension, coronary angioplasty, and spinal surgery. He had a 40 pack-year smoking history and consumed 2 to 4 alcoholic drinks per day. The results of a physical examination were unremarkable. A computedtomographic (CT) scan showed no abnormalities. An esophagoduodenoscopy (EGD) revealed gastric ulcers. He was treated successfully with omeprazole 20 mg by mouth daily.
A month later, a follow-up EGD revealed a 1.8 × 1.5 cm submucosal mass 3 cm from the gastroesophageal junction. The patient underwent a fundus wedge resection, and a submucosal mass 1.8 cm in greatest dimension was removed. Pathologic examination revealed a GIST, spindle cell type, with a mitotic rate of 36 mitoses per 50 hpf with negative margins. Immunohistochemistry was positive for CD117. An exon 11 deletion (KVV558-560NV) was present in KIT. The patient’s risk of recurrence was unclear, and his follow-up included CT scans of the abdomen and pelvis every 3 to 4 months for the first 2 years, then every 6 months for the next 2.5 years.
A CT scan about 3.5 years after primary resection revealed small nonspecific liver hypodensities that became more prominent during the next year. About 5 years after primary resection, magnetic resonance imaging (MRI) revealed several liver lesions, the largest of which measured at 1.3 cm in greatest dimension. The patient’s liver metastases were readily identified by MRI (Figure 1) and CT imaging (Figure 2A).
Discussion
Small gastric GISTs are sometimes found by endoscopy performed for unrelated reasons. Recent data suggest that the incidence of gastric GIST may be higher than previously thought. In a Japanese study of patients with gastric cancer in which 100 stomachs were systematically examined pathologically, 50 microscopic GISTs were found in 35 patients.28 Most small gastric GISTs have a low mitotic index. Few cases have been described with a high mitotic index. In a study of 1765 cases of GIST of the stomach, 8 patients had a tumor size less than 2 cm and a mitotic index greater than 5. Of those, only 6 patients had long-term follow-up, and 3 were alive without disease at 2, 17, and 20 years of follow-up.7 These limited data make it impossible to predict outcomes in patients with small gastric GIST with a high mitotic index.
For patients who are at high risk of recurrence after surgery, 3 years of adjuvant imatinib treatment compared with 1 year has been shown to improve overall survival and is the current standard of care.10,17 A study comparing 5 and 3 years of imatinib is ongoing to establish whether a longer period of adjuvant treatment is warranted. In patients with metastatic GIST, lifelong imatinib until lack of benefit is considered optimal treatment.10 All patients should undergo KIT mutation analysis. Those with the PDGFRA D842V mutation, SDH (succinate dehydrogenase) deficiency, or neurofibromatosis-related GIST should not receive adjuvant imatinib.
This case has several unusual features. The small tumor size with a very high mitotic rate is rare. Such cases have not been reported in large numbers and have therefore not been reliably incorporated into risk prediction algorithms. In addition, despite a high mitotic index, the tumor was not FDG avid on PET imaging. The diagnosis of GIST is strongly supported by the KIT mutation and response to imatinib. This particular KIT mutation in larger GISTs is associated with aggressive disease. The present case adds to the data on the biology of small gastric GISTs with a high mitotic index and suggests the mitotic index in these tumors may be a more important predictor than size.
Acknowledgment
The authors thank Michael Franklin, MS, for editorial assistance, and Sabrina Porter for media edits.
1. Corless CL, Barnett CM, Heinrich MC. Gastrointestinal stromal tumours: origin and molecular oncology. Nat Rev Cancer. 2011;11(12):865-878.
2. Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279(5350):577-580.
3. Corless CL, Ballman KV, Antonescu CR, et al. Pathologic and molecular features correlate with long-term outcome after adjuvant therapy of resected primary GI stromal tumor: the ACOSOG Z9001 trial. J Clin Oncol. 2014;32(15):1563-1570.
4. Huang J, Zheng DL, Qin FS, et al. Genetic and epigenetic silencing of SCARA5 may contribute to human hepatocellular carcinoma by activating FAK signaling. J Clin Invest. 2010;120(1):223-241.
5. Joensuu H, Vehtari A, Riihimaki J, et al. Risk of recurrence of gastrointestinal stromal tumour after surgery: an analysis of pooled population-based cohorts. Lancet Oncol. 2012;13(3):265-274.
6. Miettinen M, Lasota J. Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis. Arch Pathol Lab Med. 2006;130(10):1466-1478.
7. Miettinen M, Sobin LH, Lasota J. Gastrointestinal stromal tumors of the stomach: a clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with long-term follow-up. Am J Surg Pathol. 2005;29(1):52-68.
8. Patel S. Navigating risk stratification systems for the management of patients with GIST. Ann Surg Oncol. 2011;18(6):1698-1704.
9. Rossi S, Miceli R, Messerini L, et al. Natural history of imatinib-naive GISTs: a retrospective analysis of 929 cases with long-term follow-up and development of a survival nomogram based on mitotic index and size as continuous variables. Am J Surg Pathol. 2011;35(11):1646-1656.
10. National Comprehensive Cancer Network. Sarcoma. https://www.nccn.org. Accessed March 27, 2018.
11. Fletcher CD, Berman JJ, Corless C, et al. Diagnosis of gastrointestinal stromal tumors: a consensus approach. Int J Surg Pathol. 2002;10(2):81-89.
12. Huang HY, Li CF, Huang WW, et al. A modification of NIH consensus criteria to better distinguish the highly lethal subset of primary localized gastrointestinal stromal tumors: a subdivision of the original high-risk group on the basis of outcome. Surgery. 2007;141(6):748-756.
13. Kim MC, Yook JH, Yang HK, et al. Long-term surgical outcome of 1057 gastric GISTs according to 7th UICC/AJCC TNM system: multicenter observational study From Korea and Japan. Medicine (Baltimore). 2015;94(41):e1526.
14. Casali PG, Blay JY; ESMO/CONTICANET/EUROBONET Consensus Panel of experts. Soft tissue sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21(Suppl 5):v198-v203.
15. Joensuu H, DeMatteo RP. The management of gastrointestinal stromal tumors: a model for targeted and multidisciplinary therapy of malignancy. Annu Rev Med. 2012;63:247-258.
16. Dematteo RP, Ballman KV, Antonescu CR, et al. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet. 2009;373(9669):1097-1104.
17. Joensuu H, Eriksson M, Sundby Hall K, et al. One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial. JAMA. 2012;307(12):1265-1272.
18. Joensuu H, Rutkowski P, Nishida T, et al. KIT and PDGFRA mutations and the risk of GI stromal tumor recurrence. J Clin Oncol. 2015;33(6):634-642.
19. Fletcher CD, Berman JJ, Corless C, et al. Diagnosis of gastrointestinal stromal tumors: A consensus approach. Hum Pathol. 2002;33(5):459-465.
20. Antonescu CR, Viale A, Sarran L, et al. Gene expression in gastrointestinal stromal tumors is distinguished by KIT genotype and anatomic site. Clin Cancer Res. 2004;10(10):3282-3290.
21. Arne G, Kristiansson E, Nerman O, et al. Expression profiling of GIST: CD133 is associated with KIT exon 11 mutations, gastric location and poor prognosis. Int J Cancer. 2011;129(5):1149-1161.
22. Bertucci F, Finetti P, Ostrowski J, et al. Genomic Grade Index predicts postoperative clinical outcome of GIST. Br J Cancer. 2012;107(8):1433-1441.
23. Koon N, Schneider-Stock R, Sarlomo-Rikala M, et al. Molecular targets for tumour progression in gastrointestinal stromal tumours. Gut. 2004;53(2):235-240.
24. Lagarde P, Perot G, Kauffmann A, et al. Mitotic checkpoints and chromosome instability are strong predictors of clinical outcome in gastrointestinal stromal tumors. Clin Cancer Res. 2012;18(3):826-838.
25. Skubitz KM, Geschwind K, Xu WW, Koopmeiners JS, Skubitz AP. Gene expression identifies heterogeneity of metastatic behavior among gastrointestinal stromal tumors. J Transl Med. 2016;14:51.
26. Yamaguchi U, Nakayama R, Honda K, et al. Distinct gene expression-defined classes of gastrointestinal stromal tumor. J Clin Oncol. 2008;26(25):4100-4108.
27. Ylipaa A, Hunt KK, Yang J, et al. Integrative genomic characterization and a genomic staging system for gastrointestinal stromal tumors. Cancer. 2011;117(2):380-389.
28. Kawanowa K, Sakuma Y, Sakurai S, et al. High incidence of microscopic gastrointestinal stromal tumors in the stomach. Hum Pathol. 2006;37(12):1527-1535.
Gastrointestinal stromal tumor (GIST) is the most common soft tissue sarcoma of the gastrointestinal tract, usually arising from the interstitial cells of Cajal or similar cells in the outer wall of the gastrointestinal tract.1,2 Most GISTs have an activating mutation in KIT or platelet-derived growth factor receptor alpha (PDGFRA). Tumor size, mitotic rate, and anatomic site are the most common pathological features used to risk stratify GIST tumors.3-10 It is important to note when using such risk calculators that preoperative imatinib before determining tumor characteristics (such as mitoses per 50 high-power fields [hpf]) often changes the relevant parameters so that the same risk calculations may not apply. Tumors with a mitotic rate ≤5 mitoses per 50 hpf and a size ≤5 cm in greatest dimension have a lower recurrence rate after resection than tumors with a mitotic rate >5 mitoses per 50 hpf and a size >10 cm, and larger tumors can have a recurrence rate of up to 86%.11,12 Findings from a large observational study have suggested that the prognosis of gastric GIST in Korea and Japan may be more favorable compared with that in Western countries.13
The primary treatment of a localized primary GIST is surgical excision, but a cure is limited by recurrence.14,15 Imatinib is useful in the treatment of metastatic or recurrent GIST, and adjuvant treatment with imatinib after surgery has been shown to improve progression-free and overall survival in some cases.3,16-18 Responses to adjuvant imatinib depend on tumor sensitivity to the drug and the risk of recurrence. Drug sensitivity is largely dependent on the presence of mutations in KIT or PDGFRA.3,18 Recurrence risk is highly dependent on tumor size, tumor site, tumor rupture, and mitotic index.1,3,5,6,8,9,18,19 Findings on the use of gene expression patterns to predict recurrence risk have also been reported.20-27 However, recurrence risk is poorly understood for categories in which there are few cases with known outcomes, such as very small gastric GIST with a high mitotic index. For example, few cases of gastric GIST have been reported with a tumor size ≤2 cm, a mitotic rate >5 mitoses per 50 hpf, and adequate clinical follow-up. In such cases, it is difficult to assess the risk of recurrence.6 We report here the long-term outcome of a patient with a 1.8 cm gastric GIST with a mitotic index of 36 mitoses per 50 hpf and a KIT exon 11 mutation.
Case presentation and summary
A 69-year-old man presented with periumbilical and epigastric pain of 6-month duration. His medical history was notable for hyperlipidemia, hypertension, coronary angioplasty, and spinal surgery. He had a 40 pack-year smoking history and consumed 2 to 4 alcoholic drinks per day. The results of a physical examination were unremarkable. A computedtomographic (CT) scan showed no abnormalities. An esophagoduodenoscopy (EGD) revealed gastric ulcers. He was treated successfully with omeprazole 20 mg by mouth daily.
A month later, a follow-up EGD revealed a 1.8 × 1.5 cm submucosal mass 3 cm from the gastroesophageal junction. The patient underwent a fundus wedge resection, and a submucosal mass 1.8 cm in greatest dimension was removed. Pathologic examination revealed a GIST, spindle cell type, with a mitotic rate of 36 mitoses per 50 hpf with negative margins. Immunohistochemistry was positive for CD117. An exon 11 deletion (KVV558-560NV) was present in KIT. The patient’s risk of recurrence was unclear, and his follow-up included CT scans of the abdomen and pelvis every 3 to 4 months for the first 2 years, then every 6 months for the next 2.5 years.
A CT scan about 3.5 years after primary resection revealed small nonspecific liver hypodensities that became more prominent during the next year. About 5 years after primary resection, magnetic resonance imaging (MRI) revealed several liver lesions, the largest of which measured at 1.3 cm in greatest dimension. The patient’s liver metastases were readily identified by MRI (Figure 1) and CT imaging (Figure 2A).
Discussion
Small gastric GISTs are sometimes found by endoscopy performed for unrelated reasons. Recent data suggest that the incidence of gastric GIST may be higher than previously thought. In a Japanese study of patients with gastric cancer in which 100 stomachs were systematically examined pathologically, 50 microscopic GISTs were found in 35 patients.28 Most small gastric GISTs have a low mitotic index. Few cases have been described with a high mitotic index. In a study of 1765 cases of GIST of the stomach, 8 patients had a tumor size less than 2 cm and a mitotic index greater than 5. Of those, only 6 patients had long-term follow-up, and 3 were alive without disease at 2, 17, and 20 years of follow-up.7 These limited data make it impossible to predict outcomes in patients with small gastric GIST with a high mitotic index.
For patients who are at high risk of recurrence after surgery, 3 years of adjuvant imatinib treatment compared with 1 year has been shown to improve overall survival and is the current standard of care.10,17 A study comparing 5 and 3 years of imatinib is ongoing to establish whether a longer period of adjuvant treatment is warranted. In patients with metastatic GIST, lifelong imatinib until lack of benefit is considered optimal treatment.10 All patients should undergo KIT mutation analysis. Those with the PDGFRA D842V mutation, SDH (succinate dehydrogenase) deficiency, or neurofibromatosis-related GIST should not receive adjuvant imatinib.
This case has several unusual features. The small tumor size with a very high mitotic rate is rare. Such cases have not been reported in large numbers and have therefore not been reliably incorporated into risk prediction algorithms. In addition, despite a high mitotic index, the tumor was not FDG avid on PET imaging. The diagnosis of GIST is strongly supported by the KIT mutation and response to imatinib. This particular KIT mutation in larger GISTs is associated with aggressive disease. The present case adds to the data on the biology of small gastric GISTs with a high mitotic index and suggests the mitotic index in these tumors may be a more important predictor than size.
Acknowledgment
The authors thank Michael Franklin, MS, for editorial assistance, and Sabrina Porter for media edits.
Gastrointestinal stromal tumor (GIST) is the most common soft tissue sarcoma of the gastrointestinal tract, usually arising from the interstitial cells of Cajal or similar cells in the outer wall of the gastrointestinal tract.1,2 Most GISTs have an activating mutation in KIT or platelet-derived growth factor receptor alpha (PDGFRA). Tumor size, mitotic rate, and anatomic site are the most common pathological features used to risk stratify GIST tumors.3-10 It is important to note when using such risk calculators that preoperative imatinib before determining tumor characteristics (such as mitoses per 50 high-power fields [hpf]) often changes the relevant parameters so that the same risk calculations may not apply. Tumors with a mitotic rate ≤5 mitoses per 50 hpf and a size ≤5 cm in greatest dimension have a lower recurrence rate after resection than tumors with a mitotic rate >5 mitoses per 50 hpf and a size >10 cm, and larger tumors can have a recurrence rate of up to 86%.11,12 Findings from a large observational study have suggested that the prognosis of gastric GIST in Korea and Japan may be more favorable compared with that in Western countries.13
The primary treatment of a localized primary GIST is surgical excision, but a cure is limited by recurrence.14,15 Imatinib is useful in the treatment of metastatic or recurrent GIST, and adjuvant treatment with imatinib after surgery has been shown to improve progression-free and overall survival in some cases.3,16-18 Responses to adjuvant imatinib depend on tumor sensitivity to the drug and the risk of recurrence. Drug sensitivity is largely dependent on the presence of mutations in KIT or PDGFRA.3,18 Recurrence risk is highly dependent on tumor size, tumor site, tumor rupture, and mitotic index.1,3,5,6,8,9,18,19 Findings on the use of gene expression patterns to predict recurrence risk have also been reported.20-27 However, recurrence risk is poorly understood for categories in which there are few cases with known outcomes, such as very small gastric GIST with a high mitotic index. For example, few cases of gastric GIST have been reported with a tumor size ≤2 cm, a mitotic rate >5 mitoses per 50 hpf, and adequate clinical follow-up. In such cases, it is difficult to assess the risk of recurrence.6 We report here the long-term outcome of a patient with a 1.8 cm gastric GIST with a mitotic index of 36 mitoses per 50 hpf and a KIT exon 11 mutation.
Case presentation and summary
A 69-year-old man presented with periumbilical and epigastric pain of 6-month duration. His medical history was notable for hyperlipidemia, hypertension, coronary angioplasty, and spinal surgery. He had a 40 pack-year smoking history and consumed 2 to 4 alcoholic drinks per day. The results of a physical examination were unremarkable. A computedtomographic (CT) scan showed no abnormalities. An esophagoduodenoscopy (EGD) revealed gastric ulcers. He was treated successfully with omeprazole 20 mg by mouth daily.
A month later, a follow-up EGD revealed a 1.8 × 1.5 cm submucosal mass 3 cm from the gastroesophageal junction. The patient underwent a fundus wedge resection, and a submucosal mass 1.8 cm in greatest dimension was removed. Pathologic examination revealed a GIST, spindle cell type, with a mitotic rate of 36 mitoses per 50 hpf with negative margins. Immunohistochemistry was positive for CD117. An exon 11 deletion (KVV558-560NV) was present in KIT. The patient’s risk of recurrence was unclear, and his follow-up included CT scans of the abdomen and pelvis every 3 to 4 months for the first 2 years, then every 6 months for the next 2.5 years.
A CT scan about 3.5 years after primary resection revealed small nonspecific liver hypodensities that became more prominent during the next year. About 5 years after primary resection, magnetic resonance imaging (MRI) revealed several liver lesions, the largest of which measured at 1.3 cm in greatest dimension. The patient’s liver metastases were readily identified by MRI (Figure 1) and CT imaging (Figure 2A).
Discussion
Small gastric GISTs are sometimes found by endoscopy performed for unrelated reasons. Recent data suggest that the incidence of gastric GIST may be higher than previously thought. In a Japanese study of patients with gastric cancer in which 100 stomachs were systematically examined pathologically, 50 microscopic GISTs were found in 35 patients.28 Most small gastric GISTs have a low mitotic index. Few cases have been described with a high mitotic index. In a study of 1765 cases of GIST of the stomach, 8 patients had a tumor size less than 2 cm and a mitotic index greater than 5. Of those, only 6 patients had long-term follow-up, and 3 were alive without disease at 2, 17, and 20 years of follow-up.7 These limited data make it impossible to predict outcomes in patients with small gastric GIST with a high mitotic index.
For patients who are at high risk of recurrence after surgery, 3 years of adjuvant imatinib treatment compared with 1 year has been shown to improve overall survival and is the current standard of care.10,17 A study comparing 5 and 3 years of imatinib is ongoing to establish whether a longer period of adjuvant treatment is warranted. In patients with metastatic GIST, lifelong imatinib until lack of benefit is considered optimal treatment.10 All patients should undergo KIT mutation analysis. Those with the PDGFRA D842V mutation, SDH (succinate dehydrogenase) deficiency, or neurofibromatosis-related GIST should not receive adjuvant imatinib.
This case has several unusual features. The small tumor size with a very high mitotic rate is rare. Such cases have not been reported in large numbers and have therefore not been reliably incorporated into risk prediction algorithms. In addition, despite a high mitotic index, the tumor was not FDG avid on PET imaging. The diagnosis of GIST is strongly supported by the KIT mutation and response to imatinib. This particular KIT mutation in larger GISTs is associated with aggressive disease. The present case adds to the data on the biology of small gastric GISTs with a high mitotic index and suggests the mitotic index in these tumors may be a more important predictor than size.
Acknowledgment
The authors thank Michael Franklin, MS, for editorial assistance, and Sabrina Porter for media edits.
1. Corless CL, Barnett CM, Heinrich MC. Gastrointestinal stromal tumours: origin and molecular oncology. Nat Rev Cancer. 2011;11(12):865-878.
2. Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279(5350):577-580.
3. Corless CL, Ballman KV, Antonescu CR, et al. Pathologic and molecular features correlate with long-term outcome after adjuvant therapy of resected primary GI stromal tumor: the ACOSOG Z9001 trial. J Clin Oncol. 2014;32(15):1563-1570.
4. Huang J, Zheng DL, Qin FS, et al. Genetic and epigenetic silencing of SCARA5 may contribute to human hepatocellular carcinoma by activating FAK signaling. J Clin Invest. 2010;120(1):223-241.
5. Joensuu H, Vehtari A, Riihimaki J, et al. Risk of recurrence of gastrointestinal stromal tumour after surgery: an analysis of pooled population-based cohorts. Lancet Oncol. 2012;13(3):265-274.
6. Miettinen M, Lasota J. Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis. Arch Pathol Lab Med. 2006;130(10):1466-1478.
7. Miettinen M, Sobin LH, Lasota J. Gastrointestinal stromal tumors of the stomach: a clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with long-term follow-up. Am J Surg Pathol. 2005;29(1):52-68.
8. Patel S. Navigating risk stratification systems for the management of patients with GIST. Ann Surg Oncol. 2011;18(6):1698-1704.
9. Rossi S, Miceli R, Messerini L, et al. Natural history of imatinib-naive GISTs: a retrospective analysis of 929 cases with long-term follow-up and development of a survival nomogram based on mitotic index and size as continuous variables. Am J Surg Pathol. 2011;35(11):1646-1656.
10. National Comprehensive Cancer Network. Sarcoma. https://www.nccn.org. Accessed March 27, 2018.
11. Fletcher CD, Berman JJ, Corless C, et al. Diagnosis of gastrointestinal stromal tumors: a consensus approach. Int J Surg Pathol. 2002;10(2):81-89.
12. Huang HY, Li CF, Huang WW, et al. A modification of NIH consensus criteria to better distinguish the highly lethal subset of primary localized gastrointestinal stromal tumors: a subdivision of the original high-risk group on the basis of outcome. Surgery. 2007;141(6):748-756.
13. Kim MC, Yook JH, Yang HK, et al. Long-term surgical outcome of 1057 gastric GISTs according to 7th UICC/AJCC TNM system: multicenter observational study From Korea and Japan. Medicine (Baltimore). 2015;94(41):e1526.
14. Casali PG, Blay JY; ESMO/CONTICANET/EUROBONET Consensus Panel of experts. Soft tissue sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21(Suppl 5):v198-v203.
15. Joensuu H, DeMatteo RP. The management of gastrointestinal stromal tumors: a model for targeted and multidisciplinary therapy of malignancy. Annu Rev Med. 2012;63:247-258.
16. Dematteo RP, Ballman KV, Antonescu CR, et al. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet. 2009;373(9669):1097-1104.
17. Joensuu H, Eriksson M, Sundby Hall K, et al. One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial. JAMA. 2012;307(12):1265-1272.
18. Joensuu H, Rutkowski P, Nishida T, et al. KIT and PDGFRA mutations and the risk of GI stromal tumor recurrence. J Clin Oncol. 2015;33(6):634-642.
19. Fletcher CD, Berman JJ, Corless C, et al. Diagnosis of gastrointestinal stromal tumors: A consensus approach. Hum Pathol. 2002;33(5):459-465.
20. Antonescu CR, Viale A, Sarran L, et al. Gene expression in gastrointestinal stromal tumors is distinguished by KIT genotype and anatomic site. Clin Cancer Res. 2004;10(10):3282-3290.
21. Arne G, Kristiansson E, Nerman O, et al. Expression profiling of GIST: CD133 is associated with KIT exon 11 mutations, gastric location and poor prognosis. Int J Cancer. 2011;129(5):1149-1161.
22. Bertucci F, Finetti P, Ostrowski J, et al. Genomic Grade Index predicts postoperative clinical outcome of GIST. Br J Cancer. 2012;107(8):1433-1441.
23. Koon N, Schneider-Stock R, Sarlomo-Rikala M, et al. Molecular targets for tumour progression in gastrointestinal stromal tumours. Gut. 2004;53(2):235-240.
24. Lagarde P, Perot G, Kauffmann A, et al. Mitotic checkpoints and chromosome instability are strong predictors of clinical outcome in gastrointestinal stromal tumors. Clin Cancer Res. 2012;18(3):826-838.
25. Skubitz KM, Geschwind K, Xu WW, Koopmeiners JS, Skubitz AP. Gene expression identifies heterogeneity of metastatic behavior among gastrointestinal stromal tumors. J Transl Med. 2016;14:51.
26. Yamaguchi U, Nakayama R, Honda K, et al. Distinct gene expression-defined classes of gastrointestinal stromal tumor. J Clin Oncol. 2008;26(25):4100-4108.
27. Ylipaa A, Hunt KK, Yang J, et al. Integrative genomic characterization and a genomic staging system for gastrointestinal stromal tumors. Cancer. 2011;117(2):380-389.
28. Kawanowa K, Sakuma Y, Sakurai S, et al. High incidence of microscopic gastrointestinal stromal tumors in the stomach. Hum Pathol. 2006;37(12):1527-1535.
1. Corless CL, Barnett CM, Heinrich MC. Gastrointestinal stromal tumours: origin and molecular oncology. Nat Rev Cancer. 2011;11(12):865-878.
2. Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279(5350):577-580.
3. Corless CL, Ballman KV, Antonescu CR, et al. Pathologic and molecular features correlate with long-term outcome after adjuvant therapy of resected primary GI stromal tumor: the ACOSOG Z9001 trial. J Clin Oncol. 2014;32(15):1563-1570.
4. Huang J, Zheng DL, Qin FS, et al. Genetic and epigenetic silencing of SCARA5 may contribute to human hepatocellular carcinoma by activating FAK signaling. J Clin Invest. 2010;120(1):223-241.
5. Joensuu H, Vehtari A, Riihimaki J, et al. Risk of recurrence of gastrointestinal stromal tumour after surgery: an analysis of pooled population-based cohorts. Lancet Oncol. 2012;13(3):265-274.
6. Miettinen M, Lasota J. Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis. Arch Pathol Lab Med. 2006;130(10):1466-1478.
7. Miettinen M, Sobin LH, Lasota J. Gastrointestinal stromal tumors of the stomach: a clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with long-term follow-up. Am J Surg Pathol. 2005;29(1):52-68.
8. Patel S. Navigating risk stratification systems for the management of patients with GIST. Ann Surg Oncol. 2011;18(6):1698-1704.
9. Rossi S, Miceli R, Messerini L, et al. Natural history of imatinib-naive GISTs: a retrospective analysis of 929 cases with long-term follow-up and development of a survival nomogram based on mitotic index and size as continuous variables. Am J Surg Pathol. 2011;35(11):1646-1656.
10. National Comprehensive Cancer Network. Sarcoma. https://www.nccn.org. Accessed March 27, 2018.
11. Fletcher CD, Berman JJ, Corless C, et al. Diagnosis of gastrointestinal stromal tumors: a consensus approach. Int J Surg Pathol. 2002;10(2):81-89.
12. Huang HY, Li CF, Huang WW, et al. A modification of NIH consensus criteria to better distinguish the highly lethal subset of primary localized gastrointestinal stromal tumors: a subdivision of the original high-risk group on the basis of outcome. Surgery. 2007;141(6):748-756.
13. Kim MC, Yook JH, Yang HK, et al. Long-term surgical outcome of 1057 gastric GISTs according to 7th UICC/AJCC TNM system: multicenter observational study From Korea and Japan. Medicine (Baltimore). 2015;94(41):e1526.
14. Casali PG, Blay JY; ESMO/CONTICANET/EUROBONET Consensus Panel of experts. Soft tissue sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21(Suppl 5):v198-v203.
15. Joensuu H, DeMatteo RP. The management of gastrointestinal stromal tumors: a model for targeted and multidisciplinary therapy of malignancy. Annu Rev Med. 2012;63:247-258.
16. Dematteo RP, Ballman KV, Antonescu CR, et al. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet. 2009;373(9669):1097-1104.
17. Joensuu H, Eriksson M, Sundby Hall K, et al. One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial. JAMA. 2012;307(12):1265-1272.
18. Joensuu H, Rutkowski P, Nishida T, et al. KIT and PDGFRA mutations and the risk of GI stromal tumor recurrence. J Clin Oncol. 2015;33(6):634-642.
19. Fletcher CD, Berman JJ, Corless C, et al. Diagnosis of gastrointestinal stromal tumors: A consensus approach. Hum Pathol. 2002;33(5):459-465.
20. Antonescu CR, Viale A, Sarran L, et al. Gene expression in gastrointestinal stromal tumors is distinguished by KIT genotype and anatomic site. Clin Cancer Res. 2004;10(10):3282-3290.
21. Arne G, Kristiansson E, Nerman O, et al. Expression profiling of GIST: CD133 is associated with KIT exon 11 mutations, gastric location and poor prognosis. Int J Cancer. 2011;129(5):1149-1161.
22. Bertucci F, Finetti P, Ostrowski J, et al. Genomic Grade Index predicts postoperative clinical outcome of GIST. Br J Cancer. 2012;107(8):1433-1441.
23. Koon N, Schneider-Stock R, Sarlomo-Rikala M, et al. Molecular targets for tumour progression in gastrointestinal stromal tumours. Gut. 2004;53(2):235-240.
24. Lagarde P, Perot G, Kauffmann A, et al. Mitotic checkpoints and chromosome instability are strong predictors of clinical outcome in gastrointestinal stromal tumors. Clin Cancer Res. 2012;18(3):826-838.
25. Skubitz KM, Geschwind K, Xu WW, Koopmeiners JS, Skubitz AP. Gene expression identifies heterogeneity of metastatic behavior among gastrointestinal stromal tumors. J Transl Med. 2016;14:51.
26. Yamaguchi U, Nakayama R, Honda K, et al. Distinct gene expression-defined classes of gastrointestinal stromal tumor. J Clin Oncol. 2008;26(25):4100-4108.
27. Ylipaa A, Hunt KK, Yang J, et al. Integrative genomic characterization and a genomic staging system for gastrointestinal stromal tumors. Cancer. 2011;117(2):380-389.
28. Kawanowa K, Sakuma Y, Sakurai S, et al. High incidence of microscopic gastrointestinal stromal tumors in the stomach. Hum Pathol. 2006;37(12):1527-1535.
Striking rash in a patient with lung cancer on a checkpoint inhibitor
Lung cancer remains the most common cause of cancer death in the United States and worldwide.1 Despite advances in the treatment of the disease and development of targeted therapy, the 5-year overall survival in stage IV non–small-cell lung cancer remains poor, ranging from 6% to 10%.2 More recently, checkpoint inhibitors have had a major impact on the treatment of lung cancer. Nivolumab was the first program cell death protein-1 (PD-1) inhibitor approved for malignant melanoma.3 In July 2015, it was approved as a second-line treatment of squamous cell carcinoma of the lung.4 Since then, the use of nivolumab has extended to other malignancies such as head and neck cancer, renal cell carcinoma, and the list continues to expand. In lung cancer, it demonstrated superior overall survival of 9 months, compared with 6 months with docetaxel.4 Other checkpoint inhibitors such as pembrolizumab5 and atezolizumab6 were subsequently developed, and are also used in the treatment of lung cancer.
Serious potential autoimmune complications arise in up to 30% of patients treated with PD-1 inhibitors. Dermatologic toxicity is the most common immune-related adverse event in these patients. In addition to vitiligo, most common is a reticular maculopapular rash on the trunk and extremities. Other adverse events, such as photosensitivity, alopecia, xerosis, and hair color changes, are reported less frequently.7 We report here a case of rash at an unusual location (auricular and periauricular) with skin exfoliation mimicking other common skin conditions such as eczema and psoriasis.
Case presentation and summary
A 57-year-old woman with a history of cerebrovascular accident with residual left lower-leg paresis presented for acute onset expressive aphasia in the absence of other constitutional or neurological findings. Magnetic resonance imaging of the brain showed a posterior, left parietal lobe lesion of 1.6 cm with intralesional hemorrhage and surrounding edema suggestive of brain metastasis. The patient had a 35 pack-year history of smoking. A staging work-up with computed-tomographic (CT) scans showed a spiculated enhancing nodule in the superior segment of the right lower lobe plus mediastinal adenopathy.
The patient underwent a CT-guided core biopsy of the spiculated nodule, which was found to be consistent with adenocarcinoma of the lung. It was negative for EGFR mutation or ALK rearrangement. She received stereotactic radiosurgery to the left posterior parietal lesion, and after completion of radiation, was started on systemic chemotherapy with cisplatin plus pemetrexed for adenocarcinoma of the lung. She received 4 cycles of chemotherapy. Repeat imaging with a PET-CT showed interval increase of the mediastinal hypermetabolic lymphadenopathy with new hypermetabolic pretracheal lymph nodes and interval development of multiple liver metastases in the right and left lobes of the liver (Figure 1). She was started on second-line therapy with nivolumab at a dose of 240 mg every 2 weeks. The treatment was complicated initially by new onset grade 2 papular pruritic rash after cycle 2 of therapy. The rash involved the upper and lower extremities, sparing the palms, soles, trunk, abdomen, and the back. It resolved with treatment delay and topical steroids.
The patient resumed treatment with nivolumab after complete resolution of the rash. However, she developed grade 2 nephritis after cycle 5 with a creatinine level of 1.98 mg/dL (reference range, 0.6-1.2 mg/ dL). This was resolved after treatment with oral prednisone, at a starting dose of 1 mg/kg and tapered over 4 weeks. PET CT scans obtained after cycles 5 and 11 showed no metabolic activity in the mediastinum or the liver and markedly decreased uptake in the right lower lobe nodule, down to an SUV of 1.7 with no new nodules. An MRI of the brain was stable (Figure 2).
After cycle 16 of nivolumab, the patient developed a severe eczematous rash with excoriations at the base of both ears involving the periauricular and auricular areas bilaterally (Figure 3).
She completed 4 weeks of steroid therapy on a tapering schedule. Treatment with nivolumab was resumed afterward with no adverse autoimmune complications. At her last visit (25 months after initiating a PD-1 inhibitor), there was no clinical or radiologic evidence of lung cancer nor any of autoimmune adverse effects.
Discussion
Among multiple autoimmune complications, dermatologic toxicity is the most common immune-related adverse event, occuring in about 30% to 40% of patients7,8 and with an average onset of 3-4 weeks after initiating treatment with checkpoint inhibitors.9 In addition to vitiligo, the most common type of rash described is a reticular maculopapular rash on the trunk and extremities.10 Other findings, such as photosensitivity, alopecia, xerosis, and hair color changes, have been reported in smaller numbers. Skin exfoliation, as seen in the present case, has been reported in fewer than 1% of the cases.4 Perivascular lymphocytic infiltrates extending deep into the dermis are most likely to be seen if the lesions are biopsied. Both the location of the rash in our patient and its relapsing nature are rare and make it more interesting as it presents a diagnostic dilemma for treating physicians. Ear, nose, and throat surgeons are more likely to encounter such a complication with the expanded use of PD-1 and PD-ligand 1 inhibitors in advanced head and neck cancers. The differential diagnosis includes localized eczema, psoriatic rash, skin infection, or an autoimmune phenomenon.
The location of the rash was also of concern because there have been reports of autoimmune inner-ear disease related to immunotherapy.11 After the failure of treatment with empiric antibiotics and topical steroids, in addition to the development of a new rash on her abdomen, we concluded that this case might represent an unusual autoimmune skin complication. The resolution of the skin lesions in both locations (the ears and the abdomen) with the oral steroid therapy, supported our suspected diagnosis of autoimmune dermatitis.
It is essential that these complications are detected early and misdiagnosis is avoided because timely treatment with steroids will prevent progression to more severe problems such as Steven-Johnson syndrome, toxic epidermal necrolysis,12 or extension into the inner ear.11This case is part of a growing spectrum of other unusual cases seen with immunotherapy treatment, such as erythema nodosum-like reactions,13 bullous dermatitis,14 and psoriasiform eruptions.15 It highlights the need for an awareness of expanding dermatologic complications from immunotherapy beyond the reported common manifestations. Established guidelines and algorithms for the management of immune-related dermatologic toxicity are available to assist the physician in treatment (Table 1).16 Skin biopsy should be considered if the diagnosis remains uncertain, although starting empiric treatment with steroids is a widely acceptable approach. Reassessing the skin rash in 48 hours to 1 week after treatment initiation is crucial because steroid-refractory cases will need additional immunosuppression. Early termination of steroids is associated with higher recurrence rate, therefore tapering steroids over 4 weeks is highly recommended before resuming treatment with checkpoint inhibitors.
In summary, increased awareness among health care professionals of the common and unusual complications of immunotherapy agents is important and essential in patient care. In addition to oncologists, head and neck surgeons, pulmonologists, urologists, dermatologists, and general internists will encounter patients with immunotherapy-related complications. Patient education should be emphasized to ensure prompt investigation and treatment of complications. Finally, it is not yet clear whether the development of autoimmune reactions predicts disease response to treatment. In a series of 134 patients with lung cancer, the occurrence of autoimmune adverse events correlated with improved survival.17 More research is needed to identify prognostic and predictive biomarkers for response to immunotherapy.
Conclusion
This pattern of autoimmune dermatitis localizing to the ears is rare (<1% of cases of dermatitis). Nevertheless, it raises the awareness for dermatologic complications of immunotherapy beyond the classical reported manifestations. Prompt diagnosis and treatment is essential to avoid serious complications such as Steven-Johnson syndrome, toxic epidermal necrolysis, and potentially damage to the inner ear.
1.Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87-108.
2. Goldstraw P, Chansky K, Crowley J, et al. The IASLC Lung Cancer Staging Project: proposals for revision of the TNM stage groupings in the forthcoming (Eighth) edition of the TNM classification for lung cancer. J Thorac Oncol. 2016;11:39-51.
3. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372:320-330.
4. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373:123-135.
5. Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemo-therapy for PD- L1- positive non-small-cell lung cancer. N Engl J Med. 2016;375:1823- 1833.
6. Rittmeyer A, Barlesi F, Waterkamp D, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017;389:255-265.
7. Collins LK, Chapman MS, Carter JB, Samie FH. Cutaneous adverse events of the immune checkpoint inhibitors. Curr Prob Cancer. 2017;41:125-128.
8. Naidoo J, Page DB, Li BT, et al. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol. 2015;26(12):2375.
9. Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30(21):2691-2697.
10. Belum VR, Benhuri B, Postow MA, et al. Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor. Eur J Cancer. 2016;60:12-25.
11. Zibelman M, Pollak N, Olszanski AJ. Autoimmune inner ear disease in a melanoma patient treated with pembrolizumab. J Immunother Cancer. 2016;4:8.
12. Nayar N, Briscoe K, Penas PF. Toxic epidermal necrolysis-like reaction with severe satellite cell necrosis associated with nivolumab in a patient with ipilimumab refractory metastatic melanoma. J Immunother. 2016;39(3):149-152.
13. Tetzlaff MT, Jazaeri AA, Torres-Cabala CA, et al. Erythema nodosum-like panniculitis mimicking disease recurrence: a novel toxicity from immune checkpoint blockade therapy - report of 2 patients. J Cutan Pathol. 2017;44(12):1080-1086.
14. Naidoo J, Schindler K, Querfeld C, et al. Autoimmune bullous skin disorders with immune checkpoint inhibitors targeting PD-1 and PD-L1. Cancer Immunol Res. 2016;4(5):383-389.
15. Ohtsuka M, Miura T, Mori T, Ishikawa M, Yamamoto T. Occurrence of psoriasiform eruption during nivolumab therapy for primary oral mucosal melanoma. JAMA Dermatol. 2015;151(7):797-799.
16. Haanen JBAG, Carbonnel F, Robert C, et al; ESMO Guidelines Committee. Management of toxicities from immunotherapy: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl 4):iv119-iv142.
17. Haratani K, Hayashi H, Chiba Y, et al. Association of immune-related adverse events with nivolumab efficacy in non-small-cell lung cancer. JAMA Oncol. 2018;4(3):374-378.
Lung cancer remains the most common cause of cancer death in the United States and worldwide.1 Despite advances in the treatment of the disease and development of targeted therapy, the 5-year overall survival in stage IV non–small-cell lung cancer remains poor, ranging from 6% to 10%.2 More recently, checkpoint inhibitors have had a major impact on the treatment of lung cancer. Nivolumab was the first program cell death protein-1 (PD-1) inhibitor approved for malignant melanoma.3 In July 2015, it was approved as a second-line treatment of squamous cell carcinoma of the lung.4 Since then, the use of nivolumab has extended to other malignancies such as head and neck cancer, renal cell carcinoma, and the list continues to expand. In lung cancer, it demonstrated superior overall survival of 9 months, compared with 6 months with docetaxel.4 Other checkpoint inhibitors such as pembrolizumab5 and atezolizumab6 were subsequently developed, and are also used in the treatment of lung cancer.
Serious potential autoimmune complications arise in up to 30% of patients treated with PD-1 inhibitors. Dermatologic toxicity is the most common immune-related adverse event in these patients. In addition to vitiligo, most common is a reticular maculopapular rash on the trunk and extremities. Other adverse events, such as photosensitivity, alopecia, xerosis, and hair color changes, are reported less frequently.7 We report here a case of rash at an unusual location (auricular and periauricular) with skin exfoliation mimicking other common skin conditions such as eczema and psoriasis.
Case presentation and summary
A 57-year-old woman with a history of cerebrovascular accident with residual left lower-leg paresis presented for acute onset expressive aphasia in the absence of other constitutional or neurological findings. Magnetic resonance imaging of the brain showed a posterior, left parietal lobe lesion of 1.6 cm with intralesional hemorrhage and surrounding edema suggestive of brain metastasis. The patient had a 35 pack-year history of smoking. A staging work-up with computed-tomographic (CT) scans showed a spiculated enhancing nodule in the superior segment of the right lower lobe plus mediastinal adenopathy.
The patient underwent a CT-guided core biopsy of the spiculated nodule, which was found to be consistent with adenocarcinoma of the lung. It was negative for EGFR mutation or ALK rearrangement. She received stereotactic radiosurgery to the left posterior parietal lesion, and after completion of radiation, was started on systemic chemotherapy with cisplatin plus pemetrexed for adenocarcinoma of the lung. She received 4 cycles of chemotherapy. Repeat imaging with a PET-CT showed interval increase of the mediastinal hypermetabolic lymphadenopathy with new hypermetabolic pretracheal lymph nodes and interval development of multiple liver metastases in the right and left lobes of the liver (Figure 1). She was started on second-line therapy with nivolumab at a dose of 240 mg every 2 weeks. The treatment was complicated initially by new onset grade 2 papular pruritic rash after cycle 2 of therapy. The rash involved the upper and lower extremities, sparing the palms, soles, trunk, abdomen, and the back. It resolved with treatment delay and topical steroids.
The patient resumed treatment with nivolumab after complete resolution of the rash. However, she developed grade 2 nephritis after cycle 5 with a creatinine level of 1.98 mg/dL (reference range, 0.6-1.2 mg/ dL). This was resolved after treatment with oral prednisone, at a starting dose of 1 mg/kg and tapered over 4 weeks. PET CT scans obtained after cycles 5 and 11 showed no metabolic activity in the mediastinum or the liver and markedly decreased uptake in the right lower lobe nodule, down to an SUV of 1.7 with no new nodules. An MRI of the brain was stable (Figure 2).
After cycle 16 of nivolumab, the patient developed a severe eczematous rash with excoriations at the base of both ears involving the periauricular and auricular areas bilaterally (Figure 3).
She completed 4 weeks of steroid therapy on a tapering schedule. Treatment with nivolumab was resumed afterward with no adverse autoimmune complications. At her last visit (25 months after initiating a PD-1 inhibitor), there was no clinical or radiologic evidence of lung cancer nor any of autoimmune adverse effects.
Discussion
Among multiple autoimmune complications, dermatologic toxicity is the most common immune-related adverse event, occuring in about 30% to 40% of patients7,8 and with an average onset of 3-4 weeks after initiating treatment with checkpoint inhibitors.9 In addition to vitiligo, the most common type of rash described is a reticular maculopapular rash on the trunk and extremities.10 Other findings, such as photosensitivity, alopecia, xerosis, and hair color changes, have been reported in smaller numbers. Skin exfoliation, as seen in the present case, has been reported in fewer than 1% of the cases.4 Perivascular lymphocytic infiltrates extending deep into the dermis are most likely to be seen if the lesions are biopsied. Both the location of the rash in our patient and its relapsing nature are rare and make it more interesting as it presents a diagnostic dilemma for treating physicians. Ear, nose, and throat surgeons are more likely to encounter such a complication with the expanded use of PD-1 and PD-ligand 1 inhibitors in advanced head and neck cancers. The differential diagnosis includes localized eczema, psoriatic rash, skin infection, or an autoimmune phenomenon.
The location of the rash was also of concern because there have been reports of autoimmune inner-ear disease related to immunotherapy.11 After the failure of treatment with empiric antibiotics and topical steroids, in addition to the development of a new rash on her abdomen, we concluded that this case might represent an unusual autoimmune skin complication. The resolution of the skin lesions in both locations (the ears and the abdomen) with the oral steroid therapy, supported our suspected diagnosis of autoimmune dermatitis.
It is essential that these complications are detected early and misdiagnosis is avoided because timely treatment with steroids will prevent progression to more severe problems such as Steven-Johnson syndrome, toxic epidermal necrolysis,12 or extension into the inner ear.11This case is part of a growing spectrum of other unusual cases seen with immunotherapy treatment, such as erythema nodosum-like reactions,13 bullous dermatitis,14 and psoriasiform eruptions.15 It highlights the need for an awareness of expanding dermatologic complications from immunotherapy beyond the reported common manifestations. Established guidelines and algorithms for the management of immune-related dermatologic toxicity are available to assist the physician in treatment (Table 1).16 Skin biopsy should be considered if the diagnosis remains uncertain, although starting empiric treatment with steroids is a widely acceptable approach. Reassessing the skin rash in 48 hours to 1 week after treatment initiation is crucial because steroid-refractory cases will need additional immunosuppression. Early termination of steroids is associated with higher recurrence rate, therefore tapering steroids over 4 weeks is highly recommended before resuming treatment with checkpoint inhibitors.
In summary, increased awareness among health care professionals of the common and unusual complications of immunotherapy agents is important and essential in patient care. In addition to oncologists, head and neck surgeons, pulmonologists, urologists, dermatologists, and general internists will encounter patients with immunotherapy-related complications. Patient education should be emphasized to ensure prompt investigation and treatment of complications. Finally, it is not yet clear whether the development of autoimmune reactions predicts disease response to treatment. In a series of 134 patients with lung cancer, the occurrence of autoimmune adverse events correlated with improved survival.17 More research is needed to identify prognostic and predictive biomarkers for response to immunotherapy.
Conclusion
This pattern of autoimmune dermatitis localizing to the ears is rare (<1% of cases of dermatitis). Nevertheless, it raises the awareness for dermatologic complications of immunotherapy beyond the classical reported manifestations. Prompt diagnosis and treatment is essential to avoid serious complications such as Steven-Johnson syndrome, toxic epidermal necrolysis, and potentially damage to the inner ear.
Lung cancer remains the most common cause of cancer death in the United States and worldwide.1 Despite advances in the treatment of the disease and development of targeted therapy, the 5-year overall survival in stage IV non–small-cell lung cancer remains poor, ranging from 6% to 10%.2 More recently, checkpoint inhibitors have had a major impact on the treatment of lung cancer. Nivolumab was the first program cell death protein-1 (PD-1) inhibitor approved for malignant melanoma.3 In July 2015, it was approved as a second-line treatment of squamous cell carcinoma of the lung.4 Since then, the use of nivolumab has extended to other malignancies such as head and neck cancer, renal cell carcinoma, and the list continues to expand. In lung cancer, it demonstrated superior overall survival of 9 months, compared with 6 months with docetaxel.4 Other checkpoint inhibitors such as pembrolizumab5 and atezolizumab6 were subsequently developed, and are also used in the treatment of lung cancer.
Serious potential autoimmune complications arise in up to 30% of patients treated with PD-1 inhibitors. Dermatologic toxicity is the most common immune-related adverse event in these patients. In addition to vitiligo, most common is a reticular maculopapular rash on the trunk and extremities. Other adverse events, such as photosensitivity, alopecia, xerosis, and hair color changes, are reported less frequently.7 We report here a case of rash at an unusual location (auricular and periauricular) with skin exfoliation mimicking other common skin conditions such as eczema and psoriasis.
Case presentation and summary
A 57-year-old woman with a history of cerebrovascular accident with residual left lower-leg paresis presented for acute onset expressive aphasia in the absence of other constitutional or neurological findings. Magnetic resonance imaging of the brain showed a posterior, left parietal lobe lesion of 1.6 cm with intralesional hemorrhage and surrounding edema suggestive of brain metastasis. The patient had a 35 pack-year history of smoking. A staging work-up with computed-tomographic (CT) scans showed a spiculated enhancing nodule in the superior segment of the right lower lobe plus mediastinal adenopathy.
The patient underwent a CT-guided core biopsy of the spiculated nodule, which was found to be consistent with adenocarcinoma of the lung. It was negative for EGFR mutation or ALK rearrangement. She received stereotactic radiosurgery to the left posterior parietal lesion, and after completion of radiation, was started on systemic chemotherapy with cisplatin plus pemetrexed for adenocarcinoma of the lung. She received 4 cycles of chemotherapy. Repeat imaging with a PET-CT showed interval increase of the mediastinal hypermetabolic lymphadenopathy with new hypermetabolic pretracheal lymph nodes and interval development of multiple liver metastases in the right and left lobes of the liver (Figure 1). She was started on second-line therapy with nivolumab at a dose of 240 mg every 2 weeks. The treatment was complicated initially by new onset grade 2 papular pruritic rash after cycle 2 of therapy. The rash involved the upper and lower extremities, sparing the palms, soles, trunk, abdomen, and the back. It resolved with treatment delay and topical steroids.
The patient resumed treatment with nivolumab after complete resolution of the rash. However, she developed grade 2 nephritis after cycle 5 with a creatinine level of 1.98 mg/dL (reference range, 0.6-1.2 mg/ dL). This was resolved after treatment with oral prednisone, at a starting dose of 1 mg/kg and tapered over 4 weeks. PET CT scans obtained after cycles 5 and 11 showed no metabolic activity in the mediastinum or the liver and markedly decreased uptake in the right lower lobe nodule, down to an SUV of 1.7 with no new nodules. An MRI of the brain was stable (Figure 2).
After cycle 16 of nivolumab, the patient developed a severe eczematous rash with excoriations at the base of both ears involving the periauricular and auricular areas bilaterally (Figure 3).
She completed 4 weeks of steroid therapy on a tapering schedule. Treatment with nivolumab was resumed afterward with no adverse autoimmune complications. At her last visit (25 months after initiating a PD-1 inhibitor), there was no clinical or radiologic evidence of lung cancer nor any of autoimmune adverse effects.
Discussion
Among multiple autoimmune complications, dermatologic toxicity is the most common immune-related adverse event, occuring in about 30% to 40% of patients7,8 and with an average onset of 3-4 weeks after initiating treatment with checkpoint inhibitors.9 In addition to vitiligo, the most common type of rash described is a reticular maculopapular rash on the trunk and extremities.10 Other findings, such as photosensitivity, alopecia, xerosis, and hair color changes, have been reported in smaller numbers. Skin exfoliation, as seen in the present case, has been reported in fewer than 1% of the cases.4 Perivascular lymphocytic infiltrates extending deep into the dermis are most likely to be seen if the lesions are biopsied. Both the location of the rash in our patient and its relapsing nature are rare and make it more interesting as it presents a diagnostic dilemma for treating physicians. Ear, nose, and throat surgeons are more likely to encounter such a complication with the expanded use of PD-1 and PD-ligand 1 inhibitors in advanced head and neck cancers. The differential diagnosis includes localized eczema, psoriatic rash, skin infection, or an autoimmune phenomenon.
The location of the rash was also of concern because there have been reports of autoimmune inner-ear disease related to immunotherapy.11 After the failure of treatment with empiric antibiotics and topical steroids, in addition to the development of a new rash on her abdomen, we concluded that this case might represent an unusual autoimmune skin complication. The resolution of the skin lesions in both locations (the ears and the abdomen) with the oral steroid therapy, supported our suspected diagnosis of autoimmune dermatitis.
It is essential that these complications are detected early and misdiagnosis is avoided because timely treatment with steroids will prevent progression to more severe problems such as Steven-Johnson syndrome, toxic epidermal necrolysis,12 or extension into the inner ear.11This case is part of a growing spectrum of other unusual cases seen with immunotherapy treatment, such as erythema nodosum-like reactions,13 bullous dermatitis,14 and psoriasiform eruptions.15 It highlights the need for an awareness of expanding dermatologic complications from immunotherapy beyond the reported common manifestations. Established guidelines and algorithms for the management of immune-related dermatologic toxicity are available to assist the physician in treatment (Table 1).16 Skin biopsy should be considered if the diagnosis remains uncertain, although starting empiric treatment with steroids is a widely acceptable approach. Reassessing the skin rash in 48 hours to 1 week after treatment initiation is crucial because steroid-refractory cases will need additional immunosuppression. Early termination of steroids is associated with higher recurrence rate, therefore tapering steroids over 4 weeks is highly recommended before resuming treatment with checkpoint inhibitors.
In summary, increased awareness among health care professionals of the common and unusual complications of immunotherapy agents is important and essential in patient care. In addition to oncologists, head and neck surgeons, pulmonologists, urologists, dermatologists, and general internists will encounter patients with immunotherapy-related complications. Patient education should be emphasized to ensure prompt investigation and treatment of complications. Finally, it is not yet clear whether the development of autoimmune reactions predicts disease response to treatment. In a series of 134 patients with lung cancer, the occurrence of autoimmune adverse events correlated with improved survival.17 More research is needed to identify prognostic and predictive biomarkers for response to immunotherapy.
Conclusion
This pattern of autoimmune dermatitis localizing to the ears is rare (<1% of cases of dermatitis). Nevertheless, it raises the awareness for dermatologic complications of immunotherapy beyond the classical reported manifestations. Prompt diagnosis and treatment is essential to avoid serious complications such as Steven-Johnson syndrome, toxic epidermal necrolysis, and potentially damage to the inner ear.
1.Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87-108.
2. Goldstraw P, Chansky K, Crowley J, et al. The IASLC Lung Cancer Staging Project: proposals for revision of the TNM stage groupings in the forthcoming (Eighth) edition of the TNM classification for lung cancer. J Thorac Oncol. 2016;11:39-51.
3. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372:320-330.
4. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373:123-135.
5. Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemo-therapy for PD- L1- positive non-small-cell lung cancer. N Engl J Med. 2016;375:1823- 1833.
6. Rittmeyer A, Barlesi F, Waterkamp D, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017;389:255-265.
7. Collins LK, Chapman MS, Carter JB, Samie FH. Cutaneous adverse events of the immune checkpoint inhibitors. Curr Prob Cancer. 2017;41:125-128.
8. Naidoo J, Page DB, Li BT, et al. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol. 2015;26(12):2375.
9. Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30(21):2691-2697.
10. Belum VR, Benhuri B, Postow MA, et al. Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor. Eur J Cancer. 2016;60:12-25.
11. Zibelman M, Pollak N, Olszanski AJ. Autoimmune inner ear disease in a melanoma patient treated with pembrolizumab. J Immunother Cancer. 2016;4:8.
12. Nayar N, Briscoe K, Penas PF. Toxic epidermal necrolysis-like reaction with severe satellite cell necrosis associated with nivolumab in a patient with ipilimumab refractory metastatic melanoma. J Immunother. 2016;39(3):149-152.
13. Tetzlaff MT, Jazaeri AA, Torres-Cabala CA, et al. Erythema nodosum-like panniculitis mimicking disease recurrence: a novel toxicity from immune checkpoint blockade therapy - report of 2 patients. J Cutan Pathol. 2017;44(12):1080-1086.
14. Naidoo J, Schindler K, Querfeld C, et al. Autoimmune bullous skin disorders with immune checkpoint inhibitors targeting PD-1 and PD-L1. Cancer Immunol Res. 2016;4(5):383-389.
15. Ohtsuka M, Miura T, Mori T, Ishikawa M, Yamamoto T. Occurrence of psoriasiform eruption during nivolumab therapy for primary oral mucosal melanoma. JAMA Dermatol. 2015;151(7):797-799.
16. Haanen JBAG, Carbonnel F, Robert C, et al; ESMO Guidelines Committee. Management of toxicities from immunotherapy: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl 4):iv119-iv142.
17. Haratani K, Hayashi H, Chiba Y, et al. Association of immune-related adverse events with nivolumab efficacy in non-small-cell lung cancer. JAMA Oncol. 2018;4(3):374-378.
1.Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87-108.
2. Goldstraw P, Chansky K, Crowley J, et al. The IASLC Lung Cancer Staging Project: proposals for revision of the TNM stage groupings in the forthcoming (Eighth) edition of the TNM classification for lung cancer. J Thorac Oncol. 2016;11:39-51.
3. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372:320-330.
4. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373:123-135.
5. Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemo-therapy for PD- L1- positive non-small-cell lung cancer. N Engl J Med. 2016;375:1823- 1833.
6. Rittmeyer A, Barlesi F, Waterkamp D, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017;389:255-265.
7. Collins LK, Chapman MS, Carter JB, Samie FH. Cutaneous adverse events of the immune checkpoint inhibitors. Curr Prob Cancer. 2017;41:125-128.
8. Naidoo J, Page DB, Li BT, et al. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol. 2015;26(12):2375.
9. Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30(21):2691-2697.
10. Belum VR, Benhuri B, Postow MA, et al. Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor. Eur J Cancer. 2016;60:12-25.
11. Zibelman M, Pollak N, Olszanski AJ. Autoimmune inner ear disease in a melanoma patient treated with pembrolizumab. J Immunother Cancer. 2016;4:8.
12. Nayar N, Briscoe K, Penas PF. Toxic epidermal necrolysis-like reaction with severe satellite cell necrosis associated with nivolumab in a patient with ipilimumab refractory metastatic melanoma. J Immunother. 2016;39(3):149-152.
13. Tetzlaff MT, Jazaeri AA, Torres-Cabala CA, et al. Erythema nodosum-like panniculitis mimicking disease recurrence: a novel toxicity from immune checkpoint blockade therapy - report of 2 patients. J Cutan Pathol. 2017;44(12):1080-1086.
14. Naidoo J, Schindler K, Querfeld C, et al. Autoimmune bullous skin disorders with immune checkpoint inhibitors targeting PD-1 and PD-L1. Cancer Immunol Res. 2016;4(5):383-389.
15. Ohtsuka M, Miura T, Mori T, Ishikawa M, Yamamoto T. Occurrence of psoriasiform eruption during nivolumab therapy for primary oral mucosal melanoma. JAMA Dermatol. 2015;151(7):797-799.
16. Haanen JBAG, Carbonnel F, Robert C, et al; ESMO Guidelines Committee. Management of toxicities from immunotherapy: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl 4):iv119-iv142.
17. Haratani K, Hayashi H, Chiba Y, et al. Association of immune-related adverse events with nivolumab efficacy in non-small-cell lung cancer. JAMA Oncol. 2018;4(3):374-378.
Effective management of severe radiation dermatitis after head and neck radiotherapy
Head and neck cancer is among the most prevalent cancers in developing countries.1 Most of the patients in developing countries present in locally advanced stages, and radical radiation therapy with concurrent chemotherapy is the standard treatment.1 Radiation therapy is associated with radiation dermatitis, which causes severe symptoms in the patient and can lead to disruption of treatment, diminished rates of disease control rates, and impaired patient quality of life.2 The management of advanced radiation dermatitis is difficult and can cause consequential late morbidity to patients.2 We report here the rare case of a patient with locally advanced tonsil carcinoma who developed grade 3 radiation dermatitis while receiving radical chemoradiation. The patient’s radiation dermatitis was effectively managed with the use of a silver-containing antimicrobial dressing that yielded remarkable results, so the patient was able to resume and complete radiation therapy.
Case presentation and summary
A 48-year-old man was diagnosed with squamous cell carcinoma of the right tonsil, with bilateral neck nodes (Stage T4a N2c M0; The American Joint Committee on Cancer staging manual, 7th edition). In view of the locally advanced status of his disease, the patient was scheduled for radical radiation therapy at 70 Gy in 35 fractions over 7 weeks along with weekly chemotherapy (cisplatin 40 mg/m2). During the course of radiation therapy, the patient was monitored twice a week, and symptomatic care was done for radiation-therapy–induced toxicities.
The patient presented with grade 3 radiation dermatitis after receiving 58 Gy in 29 fractions over 5 weeks (grade 0, no change; grades 3 and 4, severe change). The radiation dermatitis involved the anterior and bilateral neck with moist desquamation of the skin (Figure 1).
It was associated with severe pain, difficulty in swallowing, and oral mucositis. The patient was subsequently admitted to the hospital; radiation therapy was stopped, and treatment was initiated to ease the effects of the radiation dermatitis. Analgesics were administered for the pain, and adequate hydration and nutritional support was administered through a nasogastric tube. The patient’s score on the Bates-Jensen Wound Assessment Tool (BWAT) for monitoring wound status was 44, which falls in extreme severity status.
In view of the extreme severity status of the radiation dermatitis, after cleaning the wound with sterile water, we covered it with an antimicrobial dressing that contained silver salt (Mepilex AG; Mölnlycke Health Care, Norcross, GA). The dressing was changed regularly every 4 days. There was a gradual improvement in the radiation dermatitis (Figure 2).
Discussion
Head and neck cancer is one of the most common cancers in developing countries.1 Most patients present with locally advanced disease, so chemoradiation is the standard treatment in these patents. Radiation therapy is associated with acute and chronic toxicities. The common radiation therapy toxicities are directed at skin and mucosa, which leads to radiation dermatitis and radiation mucositis, respectively.2 These toxicities are graded as per the Radiation Therapy Oncology Group (RTOG) criteria (Table 2).3
Acute radiation dermatitis is radiation therapy dose-dependent and manifests within a few days to weeks after starting external beam radiation therapy. Its presentation varies in severity and gradually manifests as erythema, dry or moist desquamation, and ulceration when severe. These can cause severe symptoms in the patient, leading to frequent breaks in treatment, decreased rates of disease control, and impaired patient quality of life.2 Apart from RTOG grading, radiation dermatitis can also be scored using the BWAT. This tool has been validated across many studies to score initial wound status and monitor the subsequent status numerically.4 The radiation dermatitis of the index case was scored and monitored with both RTOG and BWAT scores.The management of advanced radiation dermatitis is difficult, and it causes consequential late morbidity in patients. A range of topical agents and dressings are used to treat radiation dermatitis, but there is minimal evidence to support their use.5 The Multinational Association for Supportive Care in Cancer treatment guidelines for prevention and treatment of radiation dermatitis have also concluded that there is a lack of sufficient evidence in the literature to support the superiority for any specific intervention.6 Management of radiation dermatitis varies among practitioners because of the inconclusive evidence for available treatment options.
The use of silver-based antimicrobial dressings has been reported in the literature in the prevention and treatment of radiation dermatitis, but with mixed results.7 Such dressings absorb exudate, maintain a moist environment that promotes wound healing, fight infection, and minimize the risk for maceration, according to the product information sheet.8 Clinical study findings have shown silver to be effective in fighting many different types of pathogens, including Methicillin-resistant Staphylococcus aureus and other drug-resistant bacteria.
Aquino-Parsons and colleagues studied 196 patients with breast cancer who were undergoing whole-breast radiation therapy.9 They showed that there was no benefit of silver-containing foam dressings for the prevention of acute grade 3 radiation dermatitis compared with patients who received standard skin care (with moisturizing cream, topical steroids, saline compress, and silver sulfadiazine cream). However, the incidence of itching in the last week of radiation and 1 week after treatment completion was lower among the patients who used the dressings.
Diggelmann and colleagues studied 24 patients with breast cancer who were undergoing radiation therapy.10 Each of the erythematous areas (n = 34) was randomly divided into 2 groups; 1 group was treated with Mepilex Lite dressing and the other with standard aqueous cream. There was a significant reduction in the severity of acute radiation dermatitis in the areas on which Mepilex Lite dressings were used compared with the areas on which standard aqueous cream was used.
The patient in the present case had severe grade 3 acute radiation dermatitis with a BWAT score indicative of extreme severity. After cleaning the wound with sterile water, instead of using the standard aqueous cream on the wounds, we used Mepilex AG, an antimicrobial dressing that contains silver salt. The results were remarkable (Figure 2 and Table 2). The patient was able to restart radiation therapy, and he completed his scheduled doses.
This case highlights the effectiveness of a silver-based antimicrobial dressing in the management of advanced and severe radiation dermatitis. Further large and randomized studies are needed to test the routine use of the dressing in the management of radiation dermatitis.
1. Simard EP, Torre LA, Jemal A. International trends in head and neck cancer incidence rates: differences by country, sex and anatomic site. Oral Oncol. 2014;50(5):387-403.
2. Hymes SR, Strom EA, Fife C. Radiation dermatitis: clinical presentation, pathophysiology, and treatment 2006. J Am Acad Dermatol. 2006;54(1):28-46.
3. Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys. 1995;31(5):1341-1346.
4. Harris C, Bates-Jensen B, Parslow N, Raizman R, Singh M, Ketchen R. Bates‐Jensen wound assessment tool: pictorial guide validation project. J Wound Ostomy Continence Nurs. 2010;37(3):253-259.
5. Lucey P, Zouzias C, Franco L, Chennupati SK, Kalnicki S, McLellan BN. Practice patterns for the prophylaxis and treatment of acute radiation dermatitis in the United States. Support Care Cancer. 2017;25(9):2857-2862.
6. Wong RK, Bensadoun RJ, Boers-Doets CB, et al. Clinical practice guidelines for the prevention and treatment of acute and late radiation reactions from the MASCC Skin Toxicity Study Group. Support Care Cancer. 2013;21(10):2933-2948.
7. Vavassis P, Gelinas M, Chabot Tr J, Nguyen-Tân PF. Phase 2 study of silver leaf dressing for treatment of radiation-induced dermatitis in patients receiving radiotherapy to the head and neck. J Otolaryngology Head Neck Surg. 2008;37(1):124-129.
8. Mepilex Ag product information. Mölnlycke Health Care website. http://www.molnlycke.us/advanced-wound-care-products/antimicrobial-products/mepilex-ag/#confirm. Accessed May 3, 2018.
9. Aquino-Parsons C, Lomas S, Smith K, et al. Phase III study of silver leaf nylon dressing vs standard care for reduction of inframammary moist desquamation in patients undergoing adjuvant whole breast radiation therapy. J Med Imaging Radiat Sci. 2010;41(4):215-221.
10. Diggelmann KV, Zytkovicz AE, Tuaine JM, Bennett NC, Kelly LE, Herst PM. Mepilex Lite dressings for the management of radiation-induced erythema: a systematic inpatient controlled clinical trial. Br J Radiol. 2010;83(995):971-978.
Head and neck cancer is among the most prevalent cancers in developing countries.1 Most of the patients in developing countries present in locally advanced stages, and radical radiation therapy with concurrent chemotherapy is the standard treatment.1 Radiation therapy is associated with radiation dermatitis, which causes severe symptoms in the patient and can lead to disruption of treatment, diminished rates of disease control rates, and impaired patient quality of life.2 The management of advanced radiation dermatitis is difficult and can cause consequential late morbidity to patients.2 We report here the rare case of a patient with locally advanced tonsil carcinoma who developed grade 3 radiation dermatitis while receiving radical chemoradiation. The patient’s radiation dermatitis was effectively managed with the use of a silver-containing antimicrobial dressing that yielded remarkable results, so the patient was able to resume and complete radiation therapy.
Case presentation and summary
A 48-year-old man was diagnosed with squamous cell carcinoma of the right tonsil, with bilateral neck nodes (Stage T4a N2c M0; The American Joint Committee on Cancer staging manual, 7th edition). In view of the locally advanced status of his disease, the patient was scheduled for radical radiation therapy at 70 Gy in 35 fractions over 7 weeks along with weekly chemotherapy (cisplatin 40 mg/m2). During the course of radiation therapy, the patient was monitored twice a week, and symptomatic care was done for radiation-therapy–induced toxicities.
The patient presented with grade 3 radiation dermatitis after receiving 58 Gy in 29 fractions over 5 weeks (grade 0, no change; grades 3 and 4, severe change). The radiation dermatitis involved the anterior and bilateral neck with moist desquamation of the skin (Figure 1).
It was associated with severe pain, difficulty in swallowing, and oral mucositis. The patient was subsequently admitted to the hospital; radiation therapy was stopped, and treatment was initiated to ease the effects of the radiation dermatitis. Analgesics were administered for the pain, and adequate hydration and nutritional support was administered through a nasogastric tube. The patient’s score on the Bates-Jensen Wound Assessment Tool (BWAT) for monitoring wound status was 44, which falls in extreme severity status.
In view of the extreme severity status of the radiation dermatitis, after cleaning the wound with sterile water, we covered it with an antimicrobial dressing that contained silver salt (Mepilex AG; Mölnlycke Health Care, Norcross, GA). The dressing was changed regularly every 4 days. There was a gradual improvement in the radiation dermatitis (Figure 2).
Discussion
Head and neck cancer is one of the most common cancers in developing countries.1 Most patients present with locally advanced disease, so chemoradiation is the standard treatment in these patents. Radiation therapy is associated with acute and chronic toxicities. The common radiation therapy toxicities are directed at skin and mucosa, which leads to radiation dermatitis and radiation mucositis, respectively.2 These toxicities are graded as per the Radiation Therapy Oncology Group (RTOG) criteria (Table 2).3
Acute radiation dermatitis is radiation therapy dose-dependent and manifests within a few days to weeks after starting external beam radiation therapy. Its presentation varies in severity and gradually manifests as erythema, dry or moist desquamation, and ulceration when severe. These can cause severe symptoms in the patient, leading to frequent breaks in treatment, decreased rates of disease control, and impaired patient quality of life.2 Apart from RTOG grading, radiation dermatitis can also be scored using the BWAT. This tool has been validated across many studies to score initial wound status and monitor the subsequent status numerically.4 The radiation dermatitis of the index case was scored and monitored with both RTOG and BWAT scores.The management of advanced radiation dermatitis is difficult, and it causes consequential late morbidity in patients. A range of topical agents and dressings are used to treat radiation dermatitis, but there is minimal evidence to support their use.5 The Multinational Association for Supportive Care in Cancer treatment guidelines for prevention and treatment of radiation dermatitis have also concluded that there is a lack of sufficient evidence in the literature to support the superiority for any specific intervention.6 Management of radiation dermatitis varies among practitioners because of the inconclusive evidence for available treatment options.
The use of silver-based antimicrobial dressings has been reported in the literature in the prevention and treatment of radiation dermatitis, but with mixed results.7 Such dressings absorb exudate, maintain a moist environment that promotes wound healing, fight infection, and minimize the risk for maceration, according to the product information sheet.8 Clinical study findings have shown silver to be effective in fighting many different types of pathogens, including Methicillin-resistant Staphylococcus aureus and other drug-resistant bacteria.
Aquino-Parsons and colleagues studied 196 patients with breast cancer who were undergoing whole-breast radiation therapy.9 They showed that there was no benefit of silver-containing foam dressings for the prevention of acute grade 3 radiation dermatitis compared with patients who received standard skin care (with moisturizing cream, topical steroids, saline compress, and silver sulfadiazine cream). However, the incidence of itching in the last week of radiation and 1 week after treatment completion was lower among the patients who used the dressings.
Diggelmann and colleagues studied 24 patients with breast cancer who were undergoing radiation therapy.10 Each of the erythematous areas (n = 34) was randomly divided into 2 groups; 1 group was treated with Mepilex Lite dressing and the other with standard aqueous cream. There was a significant reduction in the severity of acute radiation dermatitis in the areas on which Mepilex Lite dressings were used compared with the areas on which standard aqueous cream was used.
The patient in the present case had severe grade 3 acute radiation dermatitis with a BWAT score indicative of extreme severity. After cleaning the wound with sterile water, instead of using the standard aqueous cream on the wounds, we used Mepilex AG, an antimicrobial dressing that contains silver salt. The results were remarkable (Figure 2 and Table 2). The patient was able to restart radiation therapy, and he completed his scheduled doses.
This case highlights the effectiveness of a silver-based antimicrobial dressing in the management of advanced and severe radiation dermatitis. Further large and randomized studies are needed to test the routine use of the dressing in the management of radiation dermatitis.
Head and neck cancer is among the most prevalent cancers in developing countries.1 Most of the patients in developing countries present in locally advanced stages, and radical radiation therapy with concurrent chemotherapy is the standard treatment.1 Radiation therapy is associated with radiation dermatitis, which causes severe symptoms in the patient and can lead to disruption of treatment, diminished rates of disease control rates, and impaired patient quality of life.2 The management of advanced radiation dermatitis is difficult and can cause consequential late morbidity to patients.2 We report here the rare case of a patient with locally advanced tonsil carcinoma who developed grade 3 radiation dermatitis while receiving radical chemoradiation. The patient’s radiation dermatitis was effectively managed with the use of a silver-containing antimicrobial dressing that yielded remarkable results, so the patient was able to resume and complete radiation therapy.
Case presentation and summary
A 48-year-old man was diagnosed with squamous cell carcinoma of the right tonsil, with bilateral neck nodes (Stage T4a N2c M0; The American Joint Committee on Cancer staging manual, 7th edition). In view of the locally advanced status of his disease, the patient was scheduled for radical radiation therapy at 70 Gy in 35 fractions over 7 weeks along with weekly chemotherapy (cisplatin 40 mg/m2). During the course of radiation therapy, the patient was monitored twice a week, and symptomatic care was done for radiation-therapy–induced toxicities.
The patient presented with grade 3 radiation dermatitis after receiving 58 Gy in 29 fractions over 5 weeks (grade 0, no change; grades 3 and 4, severe change). The radiation dermatitis involved the anterior and bilateral neck with moist desquamation of the skin (Figure 1).
It was associated with severe pain, difficulty in swallowing, and oral mucositis. The patient was subsequently admitted to the hospital; radiation therapy was stopped, and treatment was initiated to ease the effects of the radiation dermatitis. Analgesics were administered for the pain, and adequate hydration and nutritional support was administered through a nasogastric tube. The patient’s score on the Bates-Jensen Wound Assessment Tool (BWAT) for monitoring wound status was 44, which falls in extreme severity status.
In view of the extreme severity status of the radiation dermatitis, after cleaning the wound with sterile water, we covered it with an antimicrobial dressing that contained silver salt (Mepilex AG; Mölnlycke Health Care, Norcross, GA). The dressing was changed regularly every 4 days. There was a gradual improvement in the radiation dermatitis (Figure 2).
Discussion
Head and neck cancer is one of the most common cancers in developing countries.1 Most patients present with locally advanced disease, so chemoradiation is the standard treatment in these patents. Radiation therapy is associated with acute and chronic toxicities. The common radiation therapy toxicities are directed at skin and mucosa, which leads to radiation dermatitis and radiation mucositis, respectively.2 These toxicities are graded as per the Radiation Therapy Oncology Group (RTOG) criteria (Table 2).3
Acute radiation dermatitis is radiation therapy dose-dependent and manifests within a few days to weeks after starting external beam radiation therapy. Its presentation varies in severity and gradually manifests as erythema, dry or moist desquamation, and ulceration when severe. These can cause severe symptoms in the patient, leading to frequent breaks in treatment, decreased rates of disease control, and impaired patient quality of life.2 Apart from RTOG grading, radiation dermatitis can also be scored using the BWAT. This tool has been validated across many studies to score initial wound status and monitor the subsequent status numerically.4 The radiation dermatitis of the index case was scored and monitored with both RTOG and BWAT scores.The management of advanced radiation dermatitis is difficult, and it causes consequential late morbidity in patients. A range of topical agents and dressings are used to treat radiation dermatitis, but there is minimal evidence to support their use.5 The Multinational Association for Supportive Care in Cancer treatment guidelines for prevention and treatment of radiation dermatitis have also concluded that there is a lack of sufficient evidence in the literature to support the superiority for any specific intervention.6 Management of radiation dermatitis varies among practitioners because of the inconclusive evidence for available treatment options.
The use of silver-based antimicrobial dressings has been reported in the literature in the prevention and treatment of radiation dermatitis, but with mixed results.7 Such dressings absorb exudate, maintain a moist environment that promotes wound healing, fight infection, and minimize the risk for maceration, according to the product information sheet.8 Clinical study findings have shown silver to be effective in fighting many different types of pathogens, including Methicillin-resistant Staphylococcus aureus and other drug-resistant bacteria.
Aquino-Parsons and colleagues studied 196 patients with breast cancer who were undergoing whole-breast radiation therapy.9 They showed that there was no benefit of silver-containing foam dressings for the prevention of acute grade 3 radiation dermatitis compared with patients who received standard skin care (with moisturizing cream, topical steroids, saline compress, and silver sulfadiazine cream). However, the incidence of itching in the last week of radiation and 1 week after treatment completion was lower among the patients who used the dressings.
Diggelmann and colleagues studied 24 patients with breast cancer who were undergoing radiation therapy.10 Each of the erythematous areas (n = 34) was randomly divided into 2 groups; 1 group was treated with Mepilex Lite dressing and the other with standard aqueous cream. There was a significant reduction in the severity of acute radiation dermatitis in the areas on which Mepilex Lite dressings were used compared with the areas on which standard aqueous cream was used.
The patient in the present case had severe grade 3 acute radiation dermatitis with a BWAT score indicative of extreme severity. After cleaning the wound with sterile water, instead of using the standard aqueous cream on the wounds, we used Mepilex AG, an antimicrobial dressing that contains silver salt. The results were remarkable (Figure 2 and Table 2). The patient was able to restart radiation therapy, and he completed his scheduled doses.
This case highlights the effectiveness of a silver-based antimicrobial dressing in the management of advanced and severe radiation dermatitis. Further large and randomized studies are needed to test the routine use of the dressing in the management of radiation dermatitis.
1. Simard EP, Torre LA, Jemal A. International trends in head and neck cancer incidence rates: differences by country, sex and anatomic site. Oral Oncol. 2014;50(5):387-403.
2. Hymes SR, Strom EA, Fife C. Radiation dermatitis: clinical presentation, pathophysiology, and treatment 2006. J Am Acad Dermatol. 2006;54(1):28-46.
3. Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys. 1995;31(5):1341-1346.
4. Harris C, Bates-Jensen B, Parslow N, Raizman R, Singh M, Ketchen R. Bates‐Jensen wound assessment tool: pictorial guide validation project. J Wound Ostomy Continence Nurs. 2010;37(3):253-259.
5. Lucey P, Zouzias C, Franco L, Chennupati SK, Kalnicki S, McLellan BN. Practice patterns for the prophylaxis and treatment of acute radiation dermatitis in the United States. Support Care Cancer. 2017;25(9):2857-2862.
6. Wong RK, Bensadoun RJ, Boers-Doets CB, et al. Clinical practice guidelines for the prevention and treatment of acute and late radiation reactions from the MASCC Skin Toxicity Study Group. Support Care Cancer. 2013;21(10):2933-2948.
7. Vavassis P, Gelinas M, Chabot Tr J, Nguyen-Tân PF. Phase 2 study of silver leaf dressing for treatment of radiation-induced dermatitis in patients receiving radiotherapy to the head and neck. J Otolaryngology Head Neck Surg. 2008;37(1):124-129.
8. Mepilex Ag product information. Mölnlycke Health Care website. http://www.molnlycke.us/advanced-wound-care-products/antimicrobial-products/mepilex-ag/#confirm. Accessed May 3, 2018.
9. Aquino-Parsons C, Lomas S, Smith K, et al. Phase III study of silver leaf nylon dressing vs standard care for reduction of inframammary moist desquamation in patients undergoing adjuvant whole breast radiation therapy. J Med Imaging Radiat Sci. 2010;41(4):215-221.
10. Diggelmann KV, Zytkovicz AE, Tuaine JM, Bennett NC, Kelly LE, Herst PM. Mepilex Lite dressings for the management of radiation-induced erythema: a systematic inpatient controlled clinical trial. Br J Radiol. 2010;83(995):971-978.
1. Simard EP, Torre LA, Jemal A. International trends in head and neck cancer incidence rates: differences by country, sex and anatomic site. Oral Oncol. 2014;50(5):387-403.
2. Hymes SR, Strom EA, Fife C. Radiation dermatitis: clinical presentation, pathophysiology, and treatment 2006. J Am Acad Dermatol. 2006;54(1):28-46.
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