Smartphone applications (apps) using so-called artificial intelligence (AI) aimed at the general public for use on suspicious skin lesions are unreliable, said U.K. researchers reporting a systematic review.
 

These apps are providing information that could lead to “potentially life-or-death decisions,” commented co-lead author Hywel C. Williams, MD, from the Centre of Evidence Based Dermatology, University of Nottingham (England).

“The one thing you mustn’t do in a situation where early diagnosis can make a difference between life and death is you mustn’t miss the melanoma,” he said in an interview.

“These apps were missing melanomas, and that’s very worrisome,” he commented.

The review included nine studies of skin cancer smartphone apps, including two apps, SkinScan and SkinVision, that have been given Conformit Europenne (CE) marks, allowing them to be marketed across Europe. These apps are also available in Australia and New Zealand, but not in the United States.

The review found that SkinScan was not able to identify any melanomas in the one study that assessed this app, while SkinVision had a relatively low sensitivity and specificity, with 12% of cancerous or precancerous lesions missed and 21% of benign lesions wrongly identified as cancerous.

This means that among 1,000 people with a melanoma prevalence of 3%, 4 of 30 melanomas would be missed, and 200 people would be incorrectly told that a mole was of high concern, the authors estimated.

The research was published by The BMJ on Feb. 10.

“Although I was broad minded on the potential benefit of apps for diagnosing skin cancer, I am now worried given the results of our study and the overall poor quality of studies used to test these apps,” Dr. Williams commented in a statement.

Coauthor Jac Dinnes, PhD, from the Institute of Applied Health Research at the University of Birmingham (England), added it is “really disappointing that there is not better quality evidence available to judge the efficacy of these apps.”

“It is vital that health care professionals are aware of the current limitations both in the technologies and in their evaluations,” she added.

The results also highlight the limitations of the regulatory system governing smartphone apps in that they are currently not subject to assessment by bodies such as the U.K.’s Medicines and Healthcare Products Regulatory Agency (MHRA), the authors commented.

“Regulators need to become alert to the potential harm that poorly performing algorithm-based diagnostic or risk monitoring apps create,” said co-lead author Jonathan J. Deeks, PhD, also at the Institute of Applied Health Research.

“We rely on the CE mark as a sign of quality, but the current CE mark assessment processes are not fit for protecting the public against the risks that these apps present.”

Speaking in an interview, Williams lamented the poor quality of the research that had been conducted. “These studies were not good enough,” he said, adding that “there’s no excuse for really poor study design and poor reporting.”

He would like to see the regulations tightened around AI apps purporting to inform decision making for the general public and suggests that these devices should be assessed by the MHRA. “I really do think a CE mark is not enough,” he said.

The team noted that the skin cancer apps “all include disclaimers that the results should only be used as a guide and cannot replace health care advice,” through which the manufacturers “attempt to evade any responsibility for negative outcomes experienced by users.”

Nevertheless, the “poor and variable performance” of the apps revealed by their review indicates that they “have not yet shown sufficient promise to recommend their use,” they concluded.

The “official approval” implied by a CE mark “will give consumers the impression that the apps have been assessed as effective and safe,” wrote Ben Goldacre, DataLab director, Nuffield Department of Primary Care, University of Oxford (England), and colleagues in an accompanying editorial.

“The implicit assumption is that apps are similarly low-risk technology” to devices such as sticking plasters and reading glasses, they comment.

“But shortcomings in diagnostic apps can have serious implications,” they warn. The “risks include psychological harm from health anxiety or ‘cyberchondria,’ and physical harm from misdiagnosis or overdiagnosis; for clinicians there is a risk of increased workload, and changes to ethical or legal responsibilities around triage, referral, diagnosis, and treatment.” There is also potential for “inappropriate resource use, and even loss of credibility for digital technology in general.”

Details of the review

For their review, the authors searched the Cochrane Central Register on Controlled Trials, the MEDLNE, Embase, Cumulative Index to Nursing and Allied Health Literature, Conference Proceedings Citation index, Zetoc, and Science Citation Index databases, and online trial registers for studies published between August 2016 and April 2019.

From 80 studies identified, 9 met the eligibility criteria.

Of those, six studies, evaluating a total of 725 skin lesions, determined the accuracy of smartphone apps in risk stratifying suspicious skin lesions by comparing them against a histopathological reference standard diagnosis or expert follow-up.

Five of these studies aimed to detect only melanoma, while one sought to differentiate between malignant or premalignant lesions (including melanoma, basal cell carcinoma, and squamous cell carcinoma) and benign lesions.

The three remaining studies, which evaluated 407 lesions in all, compared smartphone app recommendations against a reference standard of expert recommendations for further investigation or intervention.

The researchers found the studies had a string of potential biases and limitations.

For example, only four studies recruited a consecutive sample of study participants and lesions, and only two included lesions selected by study participants, whereas five studies used lesions that had been selected by a clinician.

Three studies reported that it took 5-10 attempts to obtain an adequate image. In seven studies, it was the researchers and not the patients who used the app to photograph the lesions, and two studies used images obtained from dermatology databases.

This “raised concerns that the results of the studies were unlikely to be representative of real life use,” the authors comment.

In addition, the exclusion of unevaluable images “might have systematically inflated the diagnostic performance of the tested apps,” they add.

The independent research was supported by the National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham and is an update of one of a collection of reviews funded by the NIHR through its Cochrane Systematic Review Programme Grant.
 

This article first appeared on Medscape.com.

Smartphone applications (apps) using so-called artificial intelligence (AI) aimed at the general public for use on suspicious skin lesions are unreliable, said U.K. researchers reporting a systematic review.
 

These apps are providing information that could lead to “potentially life-or-death decisions,” commented co-lead author Hywel C. Williams, MD, from the Centre of Evidence Based Dermatology, University of Nottingham (England).

“The one thing you mustn’t do in a situation where early diagnosis can make a difference between life and death is you mustn’t miss the melanoma,” he said in an interview.

“These apps were missing melanomas, and that’s very worrisome,” he commented.

The review included nine studies of skin cancer smartphone apps, including two apps, SkinScan and SkinVision, that have been given Conformit Europenne (CE) marks, allowing them to be marketed across Europe. These apps are also available in Australia and New Zealand, but not in the United States.

The review found that SkinScan was not able to identify any melanomas in the one study that assessed this app, while SkinVision had a relatively low sensitivity and specificity, with 12% of cancerous or precancerous lesions missed and 21% of benign lesions wrongly identified as cancerous.

This means that among 1,000 people with a melanoma prevalence of 3%, 4 of 30 melanomas would be missed, and 200 people would be incorrectly told that a mole was of high concern, the authors estimated.

The research was published by The BMJ on Feb. 10.

“Although I was broad minded on the potential benefit of apps for diagnosing skin cancer, I am now worried given the results of our study and the overall poor quality of studies used to test these apps,” Dr. Williams commented in a statement.

Coauthor Jac Dinnes, PhD, from the Institute of Applied Health Research at the University of Birmingham (England), added it is “really disappointing that there is not better quality evidence available to judge the efficacy of these apps.”

“It is vital that health care professionals are aware of the current limitations both in the technologies and in their evaluations,” she added.

The results also highlight the limitations of the regulatory system governing smartphone apps in that they are currently not subject to assessment by bodies such as the U.K.’s Medicines and Healthcare Products Regulatory Agency (MHRA), the authors commented.

“Regulators need to become alert to the potential harm that poorly performing algorithm-based diagnostic or risk monitoring apps create,” said co-lead author Jonathan J. Deeks, PhD, also at the Institute of Applied Health Research.

“We rely on the CE mark as a sign of quality, but the current CE mark assessment processes are not fit for protecting the public against the risks that these apps present.”

Speaking in an interview, Williams lamented the poor quality of the research that had been conducted. “These studies were not good enough,” he said, adding that “there’s no excuse for really poor study design and poor reporting.”

He would like to see the regulations tightened around AI apps purporting to inform decision making for the general public and suggests that these devices should be assessed by the MHRA. “I really do think a CE mark is not enough,” he said.

The team noted that the skin cancer apps “all include disclaimers that the results should only be used as a guide and cannot replace health care advice,” through which the manufacturers “attempt to evade any responsibility for negative outcomes experienced by users.”

Nevertheless, the “poor and variable performance” of the apps revealed by their review indicates that they “have not yet shown sufficient promise to recommend their use,” they concluded.

The “official approval” implied by a CE mark “will give consumers the impression that the apps have been assessed as effective and safe,” wrote Ben Goldacre, DataLab director, Nuffield Department of Primary Care, University of Oxford (England), and colleagues in an accompanying editorial.

“The implicit assumption is that apps are similarly low-risk technology” to devices such as sticking plasters and reading glasses, they comment.

“But shortcomings in diagnostic apps can have serious implications,” they warn. The “risks include psychological harm from health anxiety or ‘cyberchondria,’ and physical harm from misdiagnosis or overdiagnosis; for clinicians there is a risk of increased workload, and changes to ethical or legal responsibilities around triage, referral, diagnosis, and treatment.” There is also potential for “inappropriate resource use, and even loss of credibility for digital technology in general.”

Details of the review

For their review, the authors searched the Cochrane Central Register on Controlled Trials, the MEDLNE, Embase, Cumulative Index to Nursing and Allied Health Literature, Conference Proceedings Citation index, Zetoc, and Science Citation Index databases, and online trial registers for studies published between August 2016 and April 2019.

From 80 studies identified, 9 met the eligibility criteria.

Of those, six studies, evaluating a total of 725 skin lesions, determined the accuracy of smartphone apps in risk stratifying suspicious skin lesions by comparing them against a histopathological reference standard diagnosis or expert follow-up.

Five of these studies aimed to detect only melanoma, while one sought to differentiate between malignant or premalignant lesions (including melanoma, basal cell carcinoma, and squamous cell carcinoma) and benign lesions.

The three remaining studies, which evaluated 407 lesions in all, compared smartphone app recommendations against a reference standard of expert recommendations for further investigation or intervention.

The researchers found the studies had a string of potential biases and limitations.

For example, only four studies recruited a consecutive sample of study participants and lesions, and only two included lesions selected by study participants, whereas five studies used lesions that had been selected by a clinician.

Three studies reported that it took 5-10 attempts to obtain an adequate image. In seven studies, it was the researchers and not the patients who used the app to photograph the lesions, and two studies used images obtained from dermatology databases.

This “raised concerns that the results of the studies were unlikely to be representative of real life use,” the authors comment.

In addition, the exclusion of unevaluable images “might have systematically inflated the diagnostic performance of the tested apps,” they add.

The independent research was supported by the National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham and is an update of one of a collection of reviews funded by the NIHR through its Cochrane Systematic Review Programme Grant.
 

This article first appeared on Medscape.com.

Smartphone applications (apps) using so-called artificial intelligence (AI) aimed at the general public for use on suspicious skin lesions are unreliable, said U.K. researchers reporting a systematic review.
 

These apps are providing information that could lead to “potentially life-or-death decisions,” commented co-lead author Hywel C. Williams, MD, from the Centre of Evidence Based Dermatology, University of Nottingham (England).

“The one thing you mustn’t do in a situation where early diagnosis can make a difference between life and death is you mustn’t miss the melanoma,” he said in an interview.

“These apps were missing melanomas, and that’s very worrisome,” he commented.

The review included nine studies of skin cancer smartphone apps, including two apps, SkinScan and SkinVision, that have been given Conformit Europenne (CE) marks, allowing them to be marketed across Europe. These apps are also available in Australia and New Zealand, but not in the United States.

The review found that SkinScan was not able to identify any melanomas in the one study that assessed this app, while SkinVision had a relatively low sensitivity and specificity, with 12% of cancerous or precancerous lesions missed and 21% of benign lesions wrongly identified as cancerous.

This means that among 1,000 people with a melanoma prevalence of 3%, 4 of 30 melanomas would be missed, and 200 people would be incorrectly told that a mole was of high concern, the authors estimated.

The research was published by The BMJ on Feb. 10.

“Although I was broad minded on the potential benefit of apps for diagnosing skin cancer, I am now worried given the results of our study and the overall poor quality of studies used to test these apps,” Dr. Williams commented in a statement.

Coauthor Jac Dinnes, PhD, from the Institute of Applied Health Research at the University of Birmingham (England), added it is “really disappointing that there is not better quality evidence available to judge the efficacy of these apps.”

“It is vital that health care professionals are aware of the current limitations both in the technologies and in their evaluations,” she added.

The results also highlight the limitations of the regulatory system governing smartphone apps in that they are currently not subject to assessment by bodies such as the U.K.’s Medicines and Healthcare Products Regulatory Agency (MHRA), the authors commented.

“Regulators need to become alert to the potential harm that poorly performing algorithm-based diagnostic or risk monitoring apps create,” said co-lead author Jonathan J. Deeks, PhD, also at the Institute of Applied Health Research.

“We rely on the CE mark as a sign of quality, but the current CE mark assessment processes are not fit for protecting the public against the risks that these apps present.”

Speaking in an interview, Williams lamented the poor quality of the research that had been conducted. “These studies were not good enough,” he said, adding that “there’s no excuse for really poor study design and poor reporting.”

He would like to see the regulations tightened around AI apps purporting to inform decision making for the general public and suggests that these devices should be assessed by the MHRA. “I really do think a CE mark is not enough,” he said.

The team noted that the skin cancer apps “all include disclaimers that the results should only be used as a guide and cannot replace health care advice,” through which the manufacturers “attempt to evade any responsibility for negative outcomes experienced by users.”

Nevertheless, the “poor and variable performance” of the apps revealed by their review indicates that they “have not yet shown sufficient promise to recommend their use,” they concluded.

The “official approval” implied by a CE mark “will give consumers the impression that the apps have been assessed as effective and safe,” wrote Ben Goldacre, DataLab director, Nuffield Department of Primary Care, University of Oxford (England), and colleagues in an accompanying editorial.

“The implicit assumption is that apps are similarly low-risk technology” to devices such as sticking plasters and reading glasses, they comment.

“But shortcomings in diagnostic apps can have serious implications,” they warn. The “risks include psychological harm from health anxiety or ‘cyberchondria,’ and physical harm from misdiagnosis or overdiagnosis; for clinicians there is a risk of increased workload, and changes to ethical or legal responsibilities around triage, referral, diagnosis, and treatment.” There is also potential for “inappropriate resource use, and even loss of credibility for digital technology in general.”

Details of the review

For their review, the authors searched the Cochrane Central Register on Controlled Trials, the MEDLNE, Embase, Cumulative Index to Nursing and Allied Health Literature, Conference Proceedings Citation index, Zetoc, and Science Citation Index databases, and online trial registers for studies published between August 2016 and April 2019.

From 80 studies identified, 9 met the eligibility criteria.

Of those, six studies, evaluating a total of 725 skin lesions, determined the accuracy of smartphone apps in risk stratifying suspicious skin lesions by comparing them against a histopathological reference standard diagnosis or expert follow-up.

Five of these studies aimed to detect only melanoma, while one sought to differentiate between malignant or premalignant lesions (including melanoma, basal cell carcinoma, and squamous cell carcinoma) and benign lesions.

The three remaining studies, which evaluated 407 lesions in all, compared smartphone app recommendations against a reference standard of expert recommendations for further investigation or intervention.

The researchers found the studies had a string of potential biases and limitations.

For example, only four studies recruited a consecutive sample of study participants and lesions, and only two included lesions selected by study participants, whereas five studies used lesions that had been selected by a clinician.

Three studies reported that it took 5-10 attempts to obtain an adequate image. In seven studies, it was the researchers and not the patients who used the app to photograph the lesions, and two studies used images obtained from dermatology databases.

This “raised concerns that the results of the studies were unlikely to be representative of real life use,” the authors comment.

In addition, the exclusion of unevaluable images “might have systematically inflated the diagnostic performance of the tested apps,” they add.

The independent research was supported by the National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham and is an update of one of a collection of reviews funded by the NIHR through its Cochrane Systematic Review Programme Grant.
 

This article first appeared on Medscape.com.

ORLANDO – Inotuzumab ozogamicin (InO), a CD22-targeted antibody approved for adults with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), showed promising safety and efficacy in children and young adults with R/R B-ALL in a phase 2 trial.

Of 48 patients aged 1-21 years enrolled in the Children’s Oncology Group (COG) Protocol AALL1621 and evaluable for response and toxicity after treatment with the approved adult InO dose, 19 achieved a complete response (CR) and 9 achieved a complete response with incomplete count recovery (CRi) after the first treatment cycle, for an overall CR/CRi rate of 58.3%, Maureen M. O’Brien, MD, reported at the annual meeting of the American Society of Hematology.

Of those with CR/CRi, 19 (65.5%) achieved minimal residual disease less than 0.01%, said Dr. O’Brien, a pediatric hematologist and medical director of the Leukemia/Lymphoma Program at the Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center.

Three patients had a partial response (PR), nine had stable disease (SD), and eight had progressive disease (PD), and one of each with PR and SD achieved CR/CRi after a second treatment cycle.

“Of note, two patients who were characterized as [having] progressive disease actually had marrow complete response with incomplete count recovery, but had progressive CNS disease,” she said.

Patients included in the single-arm trial had CD22-positive B-ALL, defined as B-ALL with greater than 20% of blasts expressing CD22, and were in at least their second relapse, were refractory to two prior induction regimens, or had a relapse after hematopoietic stem cell transplantation (HSCT). One exception was that patients with Down syndrome were allowed inclusion after a first relapse, she noted.

Median patient age was 9 years, four patients had CNS 3 status, three had Down syndrome, and most were heavily pretreated, with 32 in at least their second relapse.

“Most patients had significant marrow disease burden, with a median marrow blast percentage of 81%,” Dr. O’Brien said. “In terms of prior therapy, 23% had prior transplant, 23% had prior CD19 [chimeric antigen receptor (CAR)] T-cell therapy – including two patients with prior CD22 CAR T, and 29% of patients had received prior blinatumomab.”

All patients received one cycle of InO at a dose of 1.8mg/m², with .8mg/m² given on day 1 and 0.5mg/m2 given on days 8 and 15. Intrathecal therapy was determined based on CNS status.

Patients with at least stable disease at day 28 were eligible for a second cycle; those with CR or CRi received InO at a dose of 0.5 mg/m² on days 1, 8, and 15 in cycle 2, and those without CR/CRi received the same fractionated dose as in cycle 1. Patients with CR/CRi after two cycles were eligible for up to six total cycles at investigator discretion, Dr. O’Brien explained, adding that 26 of 40 patients eligible for cycle 2 proceeded, including 13 of 18 with MRD less than .01%, 6 of 10 with MRD of 0.01% or greater, and 7 of 12 with PR/SD.

After cycle 2, all 13 with MRD less than .01% maintained that MRD level, 3 of 6 with MRD of .01% or greater achieved MRD less than .01%, 2 of 7 with PR/SD achieved CRi with MRD of .01% or greater – and one of those 2 was MRD negative after a third cycle.

Seven patients received three or more cycles.

“Therapy was extremely well tolerated,” Dr. O’Brien said, noting that the most common nonhematological grade 3 or higher adverse events occurring in at least 5% of patients in cycle 1 were febrile neutropenia and infection, occurring in 27.1% and 16.7% of patients, respectively. “But toxicity was quite minimal.”

Hepatic toxicity included four cases of grade 3 alanine transaminase and one grade 3 bilirubin toxicity in cycle 1, and one grade 3 ALT in cycle 2.

“Importantly, there were no inotuzumab dose modifications or delays due to hepatic toxicity,” she said.

Nine patients experienced 11 dose-limiting toxicities in cycle 1, including 7 involving prolonged count recovery beyond day 42, which was not attributable to disease, and 4 nonhematologic events, including drug reaction with eosinophilia and systemic symptoms, bronchopulmonary hemorrhage, respiratory distress, and a postintrathecal methotrexate stroke.

Sinusoidal obstruction syndrome (SOS) developed in 5 of the 48 patients, all in patients who underwent transplant after InO treatment. Only one of the five had undergone a prior transplant. All SOS cases were grade 3 and were treated with defibrotide; four cases resolved quickly, and one was resolving at the time of death from other causes, she said.

“We found no evidence of association with age, conditioning regimen, SOS prophylaxis, cumulative InO exposure, or time from InO to transplant, bearing in mind that it is a small number of cases, so analysis is limited,” she added.

Central CD22 evaluation in 27 patients with pre– and post–cycle 1 samples showed that 11 of those patients had residual disease at the end of cycle 1.

“There is clearly a subset of patients for whom the resistance mechanism does not seem to have any bearing on CD22, as it was still highly expressed at the time of relapse, but there are a significant number of patients who have downregulation of CD22 expression or a subset of blasts that were CD22 negative at the time of relapse,” she said. “Notably, two of three patients with baseline partial CD22 expression – so less than 90% ... did not achieve a morphologic complete response, and both of these patients had KMT2A rearrangements.”

The findings are important, because 10%-20% of children and young adults with B-ALL will relapse, and therapies that can bridge patients to HSCT or CAR T-cell therapy are critical for improving outcomes, Dr. O’Brien said, explaining that InO, a humanized CD22 IgG4 antibody conjugated to calicheamicin, was approved in adults based on “the impressive results from the INNOVATE trial, compared with chemotherapy,” but prospective data on its efficacy and safety in pediatric patients are lacking.

Retrospective data from a compassionate use program in children demonstrated a response rate of 67% in a heavily pretreated population, and phase 1 data from the ITCC-059 trial presented in a poster at the ASH meeting also showed “quite impressive results,” but a major concern has been hepatic toxicity, including SOS, she said.

Given the observed safety and efficacy in the current phase 2 trial, investigation in children will continue, she said, explaining that “COG is now undertaking a phase 3 trial – AALL1732 – which will randomize patients to chemotherapy [with or without] inotuzumab for patients aged 1-25 with newly diagnosed high-risk B-ALL.”

COG AALL1621 was funded by NCTN grants, St. Baldrick’s Foundation, and Pfizer. Dr. O’Brien reported research funding from Pfizer, Celgene, AbbVie, Amgen, Bristol-Myers Squibb, and BTG.

sworcester@mdedge.com

SOURCE: O’Brien M et al. ASH 2019, Abstract 741.

ORLANDO – Inotuzumab ozogamicin (InO), a CD22-targeted antibody approved for adults with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), showed promising safety and efficacy in children and young adults with R/R B-ALL in a phase 2 trial.

Of 48 patients aged 1-21 years enrolled in the Children’s Oncology Group (COG) Protocol AALL1621 and evaluable for response and toxicity after treatment with the approved adult InO dose, 19 achieved a complete response (CR) and 9 achieved a complete response with incomplete count recovery (CRi) after the first treatment cycle, for an overall CR/CRi rate of 58.3%, Maureen M. O’Brien, MD, reported at the annual meeting of the American Society of Hematology.

Of those with CR/CRi, 19 (65.5%) achieved minimal residual disease less than 0.01%, said Dr. O’Brien, a pediatric hematologist and medical director of the Leukemia/Lymphoma Program at the Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center.

Three patients had a partial response (PR), nine had stable disease (SD), and eight had progressive disease (PD), and one of each with PR and SD achieved CR/CRi after a second treatment cycle.

“Of note, two patients who were characterized as [having] progressive disease actually had marrow complete response with incomplete count recovery, but had progressive CNS disease,” she said.

Patients included in the single-arm trial had CD22-positive B-ALL, defined as B-ALL with greater than 20% of blasts expressing CD22, and were in at least their second relapse, were refractory to two prior induction regimens, or had a relapse after hematopoietic stem cell transplantation (HSCT). One exception was that patients with Down syndrome were allowed inclusion after a first relapse, she noted.

Median patient age was 9 years, four patients had CNS 3 status, three had Down syndrome, and most were heavily pretreated, with 32 in at least their second relapse.

“Most patients had significant marrow disease burden, with a median marrow blast percentage of 81%,” Dr. O’Brien said. “In terms of prior therapy, 23% had prior transplant, 23% had prior CD19 [chimeric antigen receptor (CAR)] T-cell therapy – including two patients with prior CD22 CAR T, and 29% of patients had received prior blinatumomab.”

All patients received one cycle of InO at a dose of 1.8mg/m², with .8mg/m² given on day 1 and 0.5mg/m2 given on days 8 and 15. Intrathecal therapy was determined based on CNS status.

Patients with at least stable disease at day 28 were eligible for a second cycle; those with CR or CRi received InO at a dose of 0.5 mg/m² on days 1, 8, and 15 in cycle 2, and those without CR/CRi received the same fractionated dose as in cycle 1. Patients with CR/CRi after two cycles were eligible for up to six total cycles at investigator discretion, Dr. O’Brien explained, adding that 26 of 40 patients eligible for cycle 2 proceeded, including 13 of 18 with MRD less than .01%, 6 of 10 with MRD of 0.01% or greater, and 7 of 12 with PR/SD.

After cycle 2, all 13 with MRD less than .01% maintained that MRD level, 3 of 6 with MRD of .01% or greater achieved MRD less than .01%, 2 of 7 with PR/SD achieved CRi with MRD of .01% or greater – and one of those 2 was MRD negative after a third cycle.

Seven patients received three or more cycles.

“Therapy was extremely well tolerated,” Dr. O’Brien said, noting that the most common nonhematological grade 3 or higher adverse events occurring in at least 5% of patients in cycle 1 were febrile neutropenia and infection, occurring in 27.1% and 16.7% of patients, respectively. “But toxicity was quite minimal.”

Hepatic toxicity included four cases of grade 3 alanine transaminase and one grade 3 bilirubin toxicity in cycle 1, and one grade 3 ALT in cycle 2.

“Importantly, there were no inotuzumab dose modifications or delays due to hepatic toxicity,” she said.

Nine patients experienced 11 dose-limiting toxicities in cycle 1, including 7 involving prolonged count recovery beyond day 42, which was not attributable to disease, and 4 nonhematologic events, including drug reaction with eosinophilia and systemic symptoms, bronchopulmonary hemorrhage, respiratory distress, and a postintrathecal methotrexate stroke.

Sinusoidal obstruction syndrome (SOS) developed in 5 of the 48 patients, all in patients who underwent transplant after InO treatment. Only one of the five had undergone a prior transplant. All SOS cases were grade 3 and were treated with defibrotide; four cases resolved quickly, and one was resolving at the time of death from other causes, she said.

“We found no evidence of association with age, conditioning regimen, SOS prophylaxis, cumulative InO exposure, or time from InO to transplant, bearing in mind that it is a small number of cases, so analysis is limited,” she added.

Central CD22 evaluation in 27 patients with pre– and post–cycle 1 samples showed that 11 of those patients had residual disease at the end of cycle 1.

“There is clearly a subset of patients for whom the resistance mechanism does not seem to have any bearing on CD22, as it was still highly expressed at the time of relapse, but there are a significant number of patients who have downregulation of CD22 expression or a subset of blasts that were CD22 negative at the time of relapse,” she said. “Notably, two of three patients with baseline partial CD22 expression – so less than 90% ... did not achieve a morphologic complete response, and both of these patients had KMT2A rearrangements.”

The findings are important, because 10%-20% of children and young adults with B-ALL will relapse, and therapies that can bridge patients to HSCT or CAR T-cell therapy are critical for improving outcomes, Dr. O’Brien said, explaining that InO, a humanized CD22 IgG4 antibody conjugated to calicheamicin, was approved in adults based on “the impressive results from the INNOVATE trial, compared with chemotherapy,” but prospective data on its efficacy and safety in pediatric patients are lacking.

Retrospective data from a compassionate use program in children demonstrated a response rate of 67% in a heavily pretreated population, and phase 1 data from the ITCC-059 trial presented in a poster at the ASH meeting also showed “quite impressive results,” but a major concern has been hepatic toxicity, including SOS, she said.

Given the observed safety and efficacy in the current phase 2 trial, investigation in children will continue, she said, explaining that “COG is now undertaking a phase 3 trial – AALL1732 – which will randomize patients to chemotherapy [with or without] inotuzumab for patients aged 1-25 with newly diagnosed high-risk B-ALL.”

COG AALL1621 was funded by NCTN grants, St. Baldrick’s Foundation, and Pfizer. Dr. O’Brien reported research funding from Pfizer, Celgene, AbbVie, Amgen, Bristol-Myers Squibb, and BTG.

sworcester@mdedge.com

SOURCE: O’Brien M et al. ASH 2019, Abstract 741.

ORLANDO – Inotuzumab ozogamicin (InO), a CD22-targeted antibody approved for adults with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), showed promising safety and efficacy in children and young adults with R/R B-ALL in a phase 2 trial.

Of 48 patients aged 1-21 years enrolled in the Children’s Oncology Group (COG) Protocol AALL1621 and evaluable for response and toxicity after treatment with the approved adult InO dose, 19 achieved a complete response (CR) and 9 achieved a complete response with incomplete count recovery (CRi) after the first treatment cycle, for an overall CR/CRi rate of 58.3%, Maureen M. O’Brien, MD, reported at the annual meeting of the American Society of Hematology.

Of those with CR/CRi, 19 (65.5%) achieved minimal residual disease less than 0.01%, said Dr. O’Brien, a pediatric hematologist and medical director of the Leukemia/Lymphoma Program at the Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center.

Three patients had a partial response (PR), nine had stable disease (SD), and eight had progressive disease (PD), and one of each with PR and SD achieved CR/CRi after a second treatment cycle.

“Of note, two patients who were characterized as [having] progressive disease actually had marrow complete response with incomplete count recovery, but had progressive CNS disease,” she said.

Patients included in the single-arm trial had CD22-positive B-ALL, defined as B-ALL with greater than 20% of blasts expressing CD22, and were in at least their second relapse, were refractory to two prior induction regimens, or had a relapse after hematopoietic stem cell transplantation (HSCT). One exception was that patients with Down syndrome were allowed inclusion after a first relapse, she noted.

Median patient age was 9 years, four patients had CNS 3 status, three had Down syndrome, and most were heavily pretreated, with 32 in at least their second relapse.

“Most patients had significant marrow disease burden, with a median marrow blast percentage of 81%,” Dr. O’Brien said. “In terms of prior therapy, 23% had prior transplant, 23% had prior CD19 [chimeric antigen receptor (CAR)] T-cell therapy – including two patients with prior CD22 CAR T, and 29% of patients had received prior blinatumomab.”

All patients received one cycle of InO at a dose of 1.8mg/m², with .8mg/m² given on day 1 and 0.5mg/m2 given on days 8 and 15. Intrathecal therapy was determined based on CNS status.

Patients with at least stable disease at day 28 were eligible for a second cycle; those with CR or CRi received InO at a dose of 0.5 mg/m² on days 1, 8, and 15 in cycle 2, and those without CR/CRi received the same fractionated dose as in cycle 1. Patients with CR/CRi after two cycles were eligible for up to six total cycles at investigator discretion, Dr. O’Brien explained, adding that 26 of 40 patients eligible for cycle 2 proceeded, including 13 of 18 with MRD less than .01%, 6 of 10 with MRD of 0.01% or greater, and 7 of 12 with PR/SD.

After cycle 2, all 13 with MRD less than .01% maintained that MRD level, 3 of 6 with MRD of .01% or greater achieved MRD less than .01%, 2 of 7 with PR/SD achieved CRi with MRD of .01% or greater – and one of those 2 was MRD negative after a third cycle.

Seven patients received three or more cycles.

“Therapy was extremely well tolerated,” Dr. O’Brien said, noting that the most common nonhematological grade 3 or higher adverse events occurring in at least 5% of patients in cycle 1 were febrile neutropenia and infection, occurring in 27.1% and 16.7% of patients, respectively. “But toxicity was quite minimal.”

Hepatic toxicity included four cases of grade 3 alanine transaminase and one grade 3 bilirubin toxicity in cycle 1, and one grade 3 ALT in cycle 2.

“Importantly, there were no inotuzumab dose modifications or delays due to hepatic toxicity,” she said.

Nine patients experienced 11 dose-limiting toxicities in cycle 1, including 7 involving prolonged count recovery beyond day 42, which was not attributable to disease, and 4 nonhematologic events, including drug reaction with eosinophilia and systemic symptoms, bronchopulmonary hemorrhage, respiratory distress, and a postintrathecal methotrexate stroke.

Sinusoidal obstruction syndrome (SOS) developed in 5 of the 48 patients, all in patients who underwent transplant after InO treatment. Only one of the five had undergone a prior transplant. All SOS cases were grade 3 and were treated with defibrotide; four cases resolved quickly, and one was resolving at the time of death from other causes, she said.

“We found no evidence of association with age, conditioning regimen, SOS prophylaxis, cumulative InO exposure, or time from InO to transplant, bearing in mind that it is a small number of cases, so analysis is limited,” she added.

Central CD22 evaluation in 27 patients with pre– and post–cycle 1 samples showed that 11 of those patients had residual disease at the end of cycle 1.

“There is clearly a subset of patients for whom the resistance mechanism does not seem to have any bearing on CD22, as it was still highly expressed at the time of relapse, but there are a significant number of patients who have downregulation of CD22 expression or a subset of blasts that were CD22 negative at the time of relapse,” she said. “Notably, two of three patients with baseline partial CD22 expression – so less than 90% ... did not achieve a morphologic complete response, and both of these patients had KMT2A rearrangements.”

The findings are important, because 10%-20% of children and young adults with B-ALL will relapse, and therapies that can bridge patients to HSCT or CAR T-cell therapy are critical for improving outcomes, Dr. O’Brien said, explaining that InO, a humanized CD22 IgG4 antibody conjugated to calicheamicin, was approved in adults based on “the impressive results from the INNOVATE trial, compared with chemotherapy,” but prospective data on its efficacy and safety in pediatric patients are lacking.

Retrospective data from a compassionate use program in children demonstrated a response rate of 67% in a heavily pretreated population, and phase 1 data from the ITCC-059 trial presented in a poster at the ASH meeting also showed “quite impressive results,” but a major concern has been hepatic toxicity, including SOS, she said.

Given the observed safety and efficacy in the current phase 2 trial, investigation in children will continue, she said, explaining that “COG is now undertaking a phase 3 trial – AALL1732 – which will randomize patients to chemotherapy [with or without] inotuzumab for patients aged 1-25 with newly diagnosed high-risk B-ALL.”

COG AALL1621 was funded by NCTN grants, St. Baldrick’s Foundation, and Pfizer. Dr. O’Brien reported research funding from Pfizer, Celgene, AbbVie, Amgen, Bristol-Myers Squibb, and BTG.

sworcester@mdedge.com

SOURCE: O’Brien M et al. ASH 2019, Abstract 741.

The Centers for Disease Control and Prevention announced the number of confirmed cases of the 2019 Novel Coronavirus (2019-nCoV) in the United States has reached 13.

Gregory Twachtman/MDedge News

The latest case, announced Feb. 11, 2020, by the CDC, was in a person in California who was previously under federal quarantine because the patient had traveled to Wuhan, China.

The CDC is currently looking into who the patient may have come in contact with to understand the potential for further spread of the coronavirus.

“The contact investigation is ongoing,” CDC principal deputy director Anne Schuchat, MD, said during a Feb. 11 press conference to provide an update on coronavirus containment activities being taken by the CDC.

Dr. Schuchat also addressed issues related to the laboratory test, as the patient in California was initially thought to be negative for the coronavirus.

“With other cases around the country that we are evaluating, we have been doing serial tests to understand whether they are still infectious” and to gather other information about how results change over time, Dr. Schuchat said.

She noted that the CDC does not “have as much information as we would like on the severity of the virus,” noting that there are many cases in China with severe reactions, while the 13 cases in the United States represent a much more mild reaction to the virus so far.

With the latest case in California, she noted that there was “probably a mix-up and the original test wasn’t negative,” although she did not elaborate on what the nature of the mix-up was, stating that was all the information that she had.

In general, Dr. Schuchat touted the actions taken by the CDC and the federal government focused primarily on containing the spread of the virus in the United States, including the implementation of travel advisories, quarantining passengers returning from China, as well as the new test kits that are being distributed by the agency across the nation and around the world. She also mentioned CDC staff are being deployed around the world to monitor the spreading of the disease and highlighted the outreach efforts to keep the public informed.

Dr. Schuchat highlighted the fact that, of the 13 cases in the United States, 11 were with patients that were in Wuhan, and only 2 were because of close contact with a patient, something that she attributed to the actions being taken.

She also noted that cases in the United States have not been as severe as they have been in China, where deaths have been attributed to the coronavirus outbreak. She added that there have been only two deaths outside of mainland China attributed to the coronavirus.

“Some of the steps the CDC has taken have really put us in better shape should widespread transmission occur in the United States,” she said.

Dr. Schuchat also highlighted that the first charter flight of people quarantined after returning from Wuhan have reached the 14-day milestone and should be on their way home beginning today.

gtwachtman@mdedge.com

The Centers for Disease Control and Prevention announced the number of confirmed cases of the 2019 Novel Coronavirus (2019-nCoV) in the United States has reached 13.

Gregory Twachtman/MDedge News

The latest case, announced Feb. 11, 2020, by the CDC, was in a person in California who was previously under federal quarantine because the patient had traveled to Wuhan, China.

The CDC is currently looking into who the patient may have come in contact with to understand the potential for further spread of the coronavirus.

“The contact investigation is ongoing,” CDC principal deputy director Anne Schuchat, MD, said during a Feb. 11 press conference to provide an update on coronavirus containment activities being taken by the CDC.

Dr. Schuchat also addressed issues related to the laboratory test, as the patient in California was initially thought to be negative for the coronavirus.

“With other cases around the country that we are evaluating, we have been doing serial tests to understand whether they are still infectious” and to gather other information about how results change over time, Dr. Schuchat said.

She noted that the CDC does not “have as much information as we would like on the severity of the virus,” noting that there are many cases in China with severe reactions, while the 13 cases in the United States represent a much more mild reaction to the virus so far.

With the latest case in California, she noted that there was “probably a mix-up and the original test wasn’t negative,” although she did not elaborate on what the nature of the mix-up was, stating that was all the information that she had.

In general, Dr. Schuchat touted the actions taken by the CDC and the federal government focused primarily on containing the spread of the virus in the United States, including the implementation of travel advisories, quarantining passengers returning from China, as well as the new test kits that are being distributed by the agency across the nation and around the world. She also mentioned CDC staff are being deployed around the world to monitor the spreading of the disease and highlighted the outreach efforts to keep the public informed.

Dr. Schuchat highlighted the fact that, of the 13 cases in the United States, 11 were with patients that were in Wuhan, and only 2 were because of close contact with a patient, something that she attributed to the actions being taken.

She also noted that cases in the United States have not been as severe as they have been in China, where deaths have been attributed to the coronavirus outbreak. She added that there have been only two deaths outside of mainland China attributed to the coronavirus.

“Some of the steps the CDC has taken have really put us in better shape should widespread transmission occur in the United States,” she said.

Dr. Schuchat also highlighted that the first charter flight of people quarantined after returning from Wuhan have reached the 14-day milestone and should be on their way home beginning today.

gtwachtman@mdedge.com

The Centers for Disease Control and Prevention announced the number of confirmed cases of the 2019 Novel Coronavirus (2019-nCoV) in the United States has reached 13.

Gregory Twachtman/MDedge News

The latest case, announced Feb. 11, 2020, by the CDC, was in a person in California who was previously under federal quarantine because the patient had traveled to Wuhan, China.

The CDC is currently looking into who the patient may have come in contact with to understand the potential for further spread of the coronavirus.

“The contact investigation is ongoing,” CDC principal deputy director Anne Schuchat, MD, said during a Feb. 11 press conference to provide an update on coronavirus containment activities being taken by the CDC.

Dr. Schuchat also addressed issues related to the laboratory test, as the patient in California was initially thought to be negative for the coronavirus.

“With other cases around the country that we are evaluating, we have been doing serial tests to understand whether they are still infectious” and to gather other information about how results change over time, Dr. Schuchat said.

She noted that the CDC does not “have as much information as we would like on the severity of the virus,” noting that there are many cases in China with severe reactions, while the 13 cases in the United States represent a much more mild reaction to the virus so far.

With the latest case in California, she noted that there was “probably a mix-up and the original test wasn’t negative,” although she did not elaborate on what the nature of the mix-up was, stating that was all the information that she had.

In general, Dr. Schuchat touted the actions taken by the CDC and the federal government focused primarily on containing the spread of the virus in the United States, including the implementation of travel advisories, quarantining passengers returning from China, as well as the new test kits that are being distributed by the agency across the nation and around the world. She also mentioned CDC staff are being deployed around the world to monitor the spreading of the disease and highlighted the outreach efforts to keep the public informed.

Dr. Schuchat highlighted the fact that, of the 13 cases in the United States, 11 were with patients that were in Wuhan, and only 2 were because of close contact with a patient, something that she attributed to the actions being taken.

She also noted that cases in the United States have not been as severe as they have been in China, where deaths have been attributed to the coronavirus outbreak. She added that there have been only two deaths outside of mainland China attributed to the coronavirus.

“Some of the steps the CDC has taken have really put us in better shape should widespread transmission occur in the United States,” she said.

Dr. Schuchat also highlighted that the first charter flight of people quarantined after returning from Wuhan have reached the 14-day milestone and should be on their way home beginning today.

gtwachtman@mdedge.com

There is not enough evidence to suggest that radiofrequency radiation (RFR) associated with cell phone use causes cancer, according to a review by the Food and Drug Administration.

The FDA reviewed the published literature from 2008 to 2018 and concluded that the data don’t support any quantifiable adverse health risks from RFR. However, the evidence is not without limitations.

The FDA’s evaluation included evidence from in vivo animal studies from Jan. 1, 2008, to Aug. 1, 2018, and epidemiologic studies in humans from Jan. 1, 2008, to May 8, 2018. Both kinds of evidence had limitations, but neither produced strong indications of any causal risks from cell phone use.

The FDA noted that in vivo animal studies are limited by variability of methods and RFR exposure, which make comparisons of results difficult. These studies are also impacted by the indirect effects of temperature increases (the only currently established biological effect of RFR) and stress experienced by the animals, which make teasing out the direct effects of RFR difficult.

The FDA noted that strong epidemiologic studies can provide more relevant and accurate information than in vivo studies, but epidemiologic studies are not without limitations. For example, most have participants track and self-report their cell phone use. There’s also no way to directly track certain factors of RFR exposure, such as frequency, duration, or intensity.

Even with those caveats in mind, the FDA wrote that, “based on the studies that are described in detail in this report, there is insufficient evidence to support a causal association between RFR exposure and tumorigenesis. There is a lack of clear dose-response relationship, a lack of consistent findings or specificity, and a lack of biological mechanistic plausibility.”

The full review is available on the FDA website.

cpalmer@mdedge.com

There is not enough evidence to suggest that radiofrequency radiation (RFR) associated with cell phone use causes cancer, according to a review by the Food and Drug Administration.

The FDA reviewed the published literature from 2008 to 2018 and concluded that the data don’t support any quantifiable adverse health risks from RFR. However, the evidence is not without limitations.

The FDA’s evaluation included evidence from in vivo animal studies from Jan. 1, 2008, to Aug. 1, 2018, and epidemiologic studies in humans from Jan. 1, 2008, to May 8, 2018. Both kinds of evidence had limitations, but neither produced strong indications of any causal risks from cell phone use.

The FDA noted that in vivo animal studies are limited by variability of methods and RFR exposure, which make comparisons of results difficult. These studies are also impacted by the indirect effects of temperature increases (the only currently established biological effect of RFR) and stress experienced by the animals, which make teasing out the direct effects of RFR difficult.

The FDA noted that strong epidemiologic studies can provide more relevant and accurate information than in vivo studies, but epidemiologic studies are not without limitations. For example, most have participants track and self-report their cell phone use. There’s also no way to directly track certain factors of RFR exposure, such as frequency, duration, or intensity.

Even with those caveats in mind, the FDA wrote that, “based on the studies that are described in detail in this report, there is insufficient evidence to support a causal association between RFR exposure and tumorigenesis. There is a lack of clear dose-response relationship, a lack of consistent findings or specificity, and a lack of biological mechanistic plausibility.”

The full review is available on the FDA website.

cpalmer@mdedge.com

There is not enough evidence to suggest that radiofrequency radiation (RFR) associated with cell phone use causes cancer, according to a review by the Food and Drug Administration.

The FDA reviewed the published literature from 2008 to 2018 and concluded that the data don’t support any quantifiable adverse health risks from RFR. However, the evidence is not without limitations.

The FDA’s evaluation included evidence from in vivo animal studies from Jan. 1, 2008, to Aug. 1, 2018, and epidemiologic studies in humans from Jan. 1, 2008, to May 8, 2018. Both kinds of evidence had limitations, but neither produced strong indications of any causal risks from cell phone use.

The FDA noted that in vivo animal studies are limited by variability of methods and RFR exposure, which make comparisons of results difficult. These studies are also impacted by the indirect effects of temperature increases (the only currently established biological effect of RFR) and stress experienced by the animals, which make teasing out the direct effects of RFR difficult.

The FDA noted that strong epidemiologic studies can provide more relevant and accurate information than in vivo studies, but epidemiologic studies are not without limitations. For example, most have participants track and self-report their cell phone use. There’s also no way to directly track certain factors of RFR exposure, such as frequency, duration, or intensity.

Even with those caveats in mind, the FDA wrote that, “based on the studies that are described in detail in this report, there is insufficient evidence to support a causal association between RFR exposure and tumorigenesis. There is a lack of clear dose-response relationship, a lack of consistent findings or specificity, and a lack of biological mechanistic plausibility.”

The full review is available on the FDA website.

cpalmer@mdedge.com

The U.S. Multi-Society Task Force (USMSTF) on Colorectal Cancer recently published recommendations for endoscopic removal of precancerous colorectal lesions.

According to lead author Tonya Kaltenbach, MD, of the University of California, San Francisco, and fellow panelists, the publication aims to improve complete resection rates, which can vary widely between endoscopists; almost one out of four lesions (22.7%) may be incompletely removed by some practitioners, leading to higher rates of colorectal cancer.

“[A]lthough the majority (50%) of postcolonoscopy colon cancers [are] likely due to missed lesions, close to one-fifth of incident cancers [are] related to incomplete resection,” the panelists wrote in Gastroenterology, referring to a pooled analysis of eight surveillance studies.

The panelists’ recommendations, which were based on both evidence and clinical experience, range from specific polyp removal techniques to guidance for institution-wide quality assurance of polypectomies. Each statement is described by both strength of recommendation and level of evidence, the latter of which was determined by Grading of Recommendations, Assessment, Development, and Evaluation Ratings of Evidence (GRADE) criteria. Recommendations were written by a panel of nine experts and approved by the governing boards of the three societies they represented – the American College of Gastroenterology, the American Gastroenterological Association, and the American Society for Gastrointestinal Endoscopy. The recommendations were copublished in the March issues of the American Journal of Gastroenterology, Gastroenterology, and Gastrointestinal Endoscopy. 

Central to the publication are recommended polypectomy techniques for specific types of lesions.

“Polypectomy techniques vary widely in clinical practice,” the panelists wrote. “They are often driven by physician preference based on how they were taught and on trial and error, due to the lack of standardized training and the paucity of published evidence. In the past decade, evidence has evolved on the superiority of specific methods.”

“Optimal techniques encompass effectiveness, safety, and efficiency,” they wrote. “Colorectal lesion characteristics, including location, size, morphology, and histology, influence the optimal removal method.”

For lesions up to 9 mm, the panelists recommended cold snare polypectomy “due to high complete resection rates and safety profile.” In contrast, they recommended against both cold and hot biopsy forceps, which have been associated with higher rates of incomplete resection. Furthermore, they cautioned that hot biopsy forceps may increase risks of complications and produce inadequate tissue samples for histopathology.

For nonpedunculated lesions between 10 and 19 mm, guidance is minimal. The panelists recommended cold or hot snare polypectomy, although this statement was conditional and based on low-quality evidence.

Recommendations were more extensive for large nonpedunculated lesions (at least 20 mm). For such lesions, the panelists strongly recommended endoscopic mucosal resection (EMR). They emphasized that large lesions should be removed in the fewest possible pieces by an appropriately experienced endoscopist during a single colonoscopy session. The panelists recommended the use of a viscous injection solution with a contrast agent and adjuvant thermal ablation of the post-EMR margin. They recommended against the use of tattoo as a submucosal injection solution, and ablation of residual lesion tissue that is endoscopically visible. Additional recommendations for large lesions, including prophylactic closure of resection defects and coagulation techniques, were based on low-quality evidence.

For pedunculated lesions greater than 10 mm, the panelists recommended hot snare polypectomy. For pedunculated lesions with a head greater than 20 mm or a stalk thickness greater than 5 mm, they recommended prophylactic mechanical ligation.

Beyond lesion assessment and removal, recommendations addressed lesion marking, equipment, surveillance, and quality of polypectomy.

Concerning quality, the panelists recommended that endoscopists participate in a quality assurance program that documents adverse events, and that institutions use standardized polypectomy competency assessments, such as Cold Snare Polypectomy Competency Assessment Tool and/or Direct Observation of Polypectomy Skills.

“Focused teaching is needed to ensure the optimal endoscopic management of colorectal lesions,” the panelists wrote. They went on to suggest that “development and implementation of polypectomy quality metrics may be necessary to optimize practice and outcomes.”

“For example, the type of resection method used for the colorectal lesion removal in the procedure report should be documented, and the inclusion of adequate resection technique as a quality indicator in colorectal cancer screening programs should be considered,” they wrote. “Adverse events, including bleeding, perforation, hospital admissions, and the number of benign colorectal lesions referred for surgical management, should be measured and reported. Finally, standards for pathology preparation and reporting of lesions suspicious for submucosal invasion should be in place to provide accurate staging and management.”

The investigators reported relationships with Covidien, Ironwood, Medtronic, and others.

SOURCE: Kaltenbach T et al. Gastroenterology. 2020 Jan 18. doi: 10.1053/j.gastro.2019.12.018.

The U.S. Multi-Society Task Force (USMSTF) on Colorectal Cancer recently published recommendations for endoscopic removal of precancerous colorectal lesions.

According to lead author Tonya Kaltenbach, MD, of the University of California, San Francisco, and fellow panelists, the publication aims to improve complete resection rates, which can vary widely between endoscopists; almost one out of four lesions (22.7%) may be incompletely removed by some practitioners, leading to higher rates of colorectal cancer.

“[A]lthough the majority (50%) of postcolonoscopy colon cancers [are] likely due to missed lesions, close to one-fifth of incident cancers [are] related to incomplete resection,” the panelists wrote in Gastroenterology, referring to a pooled analysis of eight surveillance studies.

The panelists’ recommendations, which were based on both evidence and clinical experience, range from specific polyp removal techniques to guidance for institution-wide quality assurance of polypectomies. Each statement is described by both strength of recommendation and level of evidence, the latter of which was determined by Grading of Recommendations, Assessment, Development, and Evaluation Ratings of Evidence (GRADE) criteria. Recommendations were written by a panel of nine experts and approved by the governing boards of the three societies they represented – the American College of Gastroenterology, the American Gastroenterological Association, and the American Society for Gastrointestinal Endoscopy. The recommendations were copublished in the March issues of the American Journal of Gastroenterology, Gastroenterology, and Gastrointestinal Endoscopy. 

Central to the publication are recommended polypectomy techniques for specific types of lesions.

“Polypectomy techniques vary widely in clinical practice,” the panelists wrote. “They are often driven by physician preference based on how they were taught and on trial and error, due to the lack of standardized training and the paucity of published evidence. In the past decade, evidence has evolved on the superiority of specific methods.”

“Optimal techniques encompass effectiveness, safety, and efficiency,” they wrote. “Colorectal lesion characteristics, including location, size, morphology, and histology, influence the optimal removal method.”

For lesions up to 9 mm, the panelists recommended cold snare polypectomy “due to high complete resection rates and safety profile.” In contrast, they recommended against both cold and hot biopsy forceps, which have been associated with higher rates of incomplete resection. Furthermore, they cautioned that hot biopsy forceps may increase risks of complications and produce inadequate tissue samples for histopathology.

For nonpedunculated lesions between 10 and 19 mm, guidance is minimal. The panelists recommended cold or hot snare polypectomy, although this statement was conditional and based on low-quality evidence.

Recommendations were more extensive for large nonpedunculated lesions (at least 20 mm). For such lesions, the panelists strongly recommended endoscopic mucosal resection (EMR). They emphasized that large lesions should be removed in the fewest possible pieces by an appropriately experienced endoscopist during a single colonoscopy session. The panelists recommended the use of a viscous injection solution with a contrast agent and adjuvant thermal ablation of the post-EMR margin. They recommended against the use of tattoo as a submucosal injection solution, and ablation of residual lesion tissue that is endoscopically visible. Additional recommendations for large lesions, including prophylactic closure of resection defects and coagulation techniques, were based on low-quality evidence.

For pedunculated lesions greater than 10 mm, the panelists recommended hot snare polypectomy. For pedunculated lesions with a head greater than 20 mm or a stalk thickness greater than 5 mm, they recommended prophylactic mechanical ligation.

Beyond lesion assessment and removal, recommendations addressed lesion marking, equipment, surveillance, and quality of polypectomy.

Concerning quality, the panelists recommended that endoscopists participate in a quality assurance program that documents adverse events, and that institutions use standardized polypectomy competency assessments, such as Cold Snare Polypectomy Competency Assessment Tool and/or Direct Observation of Polypectomy Skills.

“Focused teaching is needed to ensure the optimal endoscopic management of colorectal lesions,” the panelists wrote. They went on to suggest that “development and implementation of polypectomy quality metrics may be necessary to optimize practice and outcomes.”

“For example, the type of resection method used for the colorectal lesion removal in the procedure report should be documented, and the inclusion of adequate resection technique as a quality indicator in colorectal cancer screening programs should be considered,” they wrote. “Adverse events, including bleeding, perforation, hospital admissions, and the number of benign colorectal lesions referred for surgical management, should be measured and reported. Finally, standards for pathology preparation and reporting of lesions suspicious for submucosal invasion should be in place to provide accurate staging and management.”

The investigators reported relationships with Covidien, Ironwood, Medtronic, and others.

SOURCE: Kaltenbach T et al. Gastroenterology. 2020 Jan 18. doi: 10.1053/j.gastro.2019.12.018.

The U.S. Multi-Society Task Force (USMSTF) on Colorectal Cancer recently published recommendations for endoscopic removal of precancerous colorectal lesions.

According to lead author Tonya Kaltenbach, MD, of the University of California, San Francisco, and fellow panelists, the publication aims to improve complete resection rates, which can vary widely between endoscopists; almost one out of four lesions (22.7%) may be incompletely removed by some practitioners, leading to higher rates of colorectal cancer.

“[A]lthough the majority (50%) of postcolonoscopy colon cancers [are] likely due to missed lesions, close to one-fifth of incident cancers [are] related to incomplete resection,” the panelists wrote in Gastroenterology, referring to a pooled analysis of eight surveillance studies.

The panelists’ recommendations, which were based on both evidence and clinical experience, range from specific polyp removal techniques to guidance for institution-wide quality assurance of polypectomies. Each statement is described by both strength of recommendation and level of evidence, the latter of which was determined by Grading of Recommendations, Assessment, Development, and Evaluation Ratings of Evidence (GRADE) criteria. Recommendations were written by a panel of nine experts and approved by the governing boards of the three societies they represented – the American College of Gastroenterology, the American Gastroenterological Association, and the American Society for Gastrointestinal Endoscopy. The recommendations were copublished in the March issues of the American Journal of Gastroenterology, Gastroenterology, and Gastrointestinal Endoscopy. 

Central to the publication are recommended polypectomy techniques for specific types of lesions.

“Polypectomy techniques vary widely in clinical practice,” the panelists wrote. “They are often driven by physician preference based on how they were taught and on trial and error, due to the lack of standardized training and the paucity of published evidence. In the past decade, evidence has evolved on the superiority of specific methods.”

“Optimal techniques encompass effectiveness, safety, and efficiency,” they wrote. “Colorectal lesion characteristics, including location, size, morphology, and histology, influence the optimal removal method.”

For lesions up to 9 mm, the panelists recommended cold snare polypectomy “due to high complete resection rates and safety profile.” In contrast, they recommended against both cold and hot biopsy forceps, which have been associated with higher rates of incomplete resection. Furthermore, they cautioned that hot biopsy forceps may increase risks of complications and produce inadequate tissue samples for histopathology.

For nonpedunculated lesions between 10 and 19 mm, guidance is minimal. The panelists recommended cold or hot snare polypectomy, although this statement was conditional and based on low-quality evidence.

Recommendations were more extensive for large nonpedunculated lesions (at least 20 mm). For such lesions, the panelists strongly recommended endoscopic mucosal resection (EMR). They emphasized that large lesions should be removed in the fewest possible pieces by an appropriately experienced endoscopist during a single colonoscopy session. The panelists recommended the use of a viscous injection solution with a contrast agent and adjuvant thermal ablation of the post-EMR margin. They recommended against the use of tattoo as a submucosal injection solution, and ablation of residual lesion tissue that is endoscopically visible. Additional recommendations for large lesions, including prophylactic closure of resection defects and coagulation techniques, were based on low-quality evidence.

For pedunculated lesions greater than 10 mm, the panelists recommended hot snare polypectomy. For pedunculated lesions with a head greater than 20 mm or a stalk thickness greater than 5 mm, they recommended prophylactic mechanical ligation.

Beyond lesion assessment and removal, recommendations addressed lesion marking, equipment, surveillance, and quality of polypectomy.

Concerning quality, the panelists recommended that endoscopists participate in a quality assurance program that documents adverse events, and that institutions use standardized polypectomy competency assessments, such as Cold Snare Polypectomy Competency Assessment Tool and/or Direct Observation of Polypectomy Skills.

“Focused teaching is needed to ensure the optimal endoscopic management of colorectal lesions,” the panelists wrote. They went on to suggest that “development and implementation of polypectomy quality metrics may be necessary to optimize practice and outcomes.”

“For example, the type of resection method used for the colorectal lesion removal in the procedure report should be documented, and the inclusion of adequate resection technique as a quality indicator in colorectal cancer screening programs should be considered,” they wrote. “Adverse events, including bleeding, perforation, hospital admissions, and the number of benign colorectal lesions referred for surgical management, should be measured and reported. Finally, standards for pathology preparation and reporting of lesions suspicious for submucosal invasion should be in place to provide accurate staging and management.”

The investigators reported relationships with Covidien, Ironwood, Medtronic, and others.

SOURCE: Kaltenbach T et al. Gastroenterology. 2020 Jan 18. doi: 10.1053/j.gastro.2019.12.018.

The CHEST 2020 Scientific Program Committee has been working tirelessly to select the best and most clinically relevant sessions for the upcoming meeting. CHEST would like to extend a heartfelt thank you to all that actively participated in grading, curriculum group calls, the live meeting in February, and all the homework in between. We’re not done, but your work has been instrumental in making the CHEST Annual Meeting 2020 a success.

The CHEST 2020 Scientific Program Committee has been working tirelessly to select the best and most clinically relevant sessions for the upcoming meeting. CHEST would like to extend a heartfelt thank you to all that actively participated in grading, curriculum group calls, the live meeting in February, and all the homework in between. We’re not done, but your work has been instrumental in making the CHEST Annual Meeting 2020 a success.

The CHEST 2020 Scientific Program Committee has been working tirelessly to select the best and most clinically relevant sessions for the upcoming meeting. CHEST would like to extend a heartfelt thank you to all that actively participated in grading, curriculum group calls, the live meeting in February, and all the homework in between. We’re not done, but your work has been instrumental in making the CHEST Annual Meeting 2020 a success.

To the Editor:

Hydralazine-induced antineutrophil cytoplasmic antibody vasculitis (HIAV) is a rare side effect that may develop in patients treated with hydralazine. Without early recognition and hydralazine cessation, patients often develop acute renal failure and pulmonary hemorrhage that may result in death. We present a case of HIAV.

A 67-year-old woman presented with progressive, tense, hemorrhagic, and necrotic bullae on both sides of the face and neck as well as the extremities of 2 weeks’ duration. She had a history of hypertension and a thyroid nodule after unilateral thyroid lobectomy. A review of symptoms was positive for worsening dyspnea and progressive generalized weakness. Noteworthy medications included amlodipine, metoprolol, levothyroxine, and oral hydralazine 75 mg 3 times daily for 13 months.

Bullae first appeared on the patient’s scalp and quickly progressed with a cephalocaudal pattern with a propensity for the eyes, nostrils, and labial mucosa (Figure 1). The tongue was covered by an eschar, and she had diffuse periorbital edema. Additionally, concentric purpuric patches were noted on the thighs and lower legs (Figure 2).

While hospitalized, she developed pulmonary hemorrhages and a progressive decline in respiratory status. She subsequently was admitted to the medical intensive care unit. Aggressive support was administered, and several skin biopsy specimens were obtained along with an endobronchial biopsy of the right middle lobe.

Skin histopathology revealed a necrotic vasculitis (Figure 3). Direct immunofluorescence was not performed. Lung histopathology showed fragments of bronchial tissue with acute and chronic inflammation, focal necrosis, granulation tissue formation, edema, and squamous metaplasia. Together with the clinical history, these findings were consistent with HIAV.

Hydralazine was first introduced in 1951 for adjunctive hypertension therapy due to its vasodilation effects.^1-3 Since its introduction, it has been implicated in 2 important disease processes: HIAV and hydralazine-induced lupus.

Hydralazine-induced ANCA vasculitis was first documented in 1980; by 2011, multiple cases had been reported.^1-7 Hydralazine-induced ANCA vasculitis has occurred in patients aged 11 to 79 years taking 50 to 300 mg daily. Symptom onset varies from 6 months to 14 years, with a mean exposure duration of 4.7 years and mean daily dose of 142 mg.^1-7

Clinical manifestations range from less specific, such as fever, malaise, arthralgia, myalgia, and weight loss, to single tissue or organ involvement that may be fatal. The most frequent clinical features include kidney involvement (81%), cutaneous vasculitis (25%), arthralgia (24%), and pleuropulmonary involvement (19%). Cutaneous manifestations include but are not limited to palpable lower extremity purpura; morbilliform eruptions; and hemorrhagic blisters on the lower legs, arms, trunk, nasal septum, and uvula.^1-4,8

The most commonly affected organ is the kidney, which commonly presents as hematuria, proteinuria, and elevated serum creatinine level. Histopathologically, patients most likely will have necrotizing and crescentic glomerulonephritis that is pauci-immune by immunofluorescence.^7,9 The lungs are the next most commonly affected organ, with a classic presentation of cough, dyspnea, and hemoptysis in the setting of intra-alveolar hemorrhage.^6,8 When both the kidneys and lungs are involved, the patient is said to have pulmonary-renal syndrome that is characterized by lung infiltrates or nodules with or without hemorrhage, hemoptysis, and pleuritis in the setting of glomerulonephritis.^1,6

Clear data on incidence and prevalence of HIAV does not exist due to the rarity of the disease and the lack of prospective studies. To identify a clear incidence and prevalence, prospective longitudinal studies with larger cohorts along with better recognition and diagnosis are needed.^2,8,10 A few predisposing risk factors have been identified, including older age, a cumulative dose of 100 g at the time of presentation, female sex, a history of thyroid disease, HLA-DR4 genotypes, slow hepatic acetylation, and the null gene for C4.^1,3,5,9-11 Our patient was an older woman with a history of thyroid disease who had been taking oral hydralazine 75 mg 3 times daily for 13 months. During this 13-month duration, she had no dose adjustments.

Currently, the pathomechanism for HIAV is unclear and may be multifactorial. There are 4 main theories^2,8-10,12,13:

1. Hydralazine and its metabolites accumulate inside neutrophils, then subsequently bind and alter the configuration of myeloperoxidase (MPO). This alteration leads to spreading of the autoimmune response to other autoantigens, making neutrophil proteins (eg, elastase, lactoferrin, nuclear antigens) immunogenic.
2. Hydralazine binds MPO in neutrophils, creating cytotoxic products that induce neutrophil apoptosis. Neutrophil apoptosis without priming then results in ANCA antigen presence on the neutrophil cell membrane and the formation of MPO-ANCA. Myeloperoxidase-ANCA then binds to these membrane-bound antigens that cause self-perpetuating, constitutive activation through cross-linking with proteinase 3 or MPO and Fcγ receptors.
3. Activated neutrophils in the presence of hydrogen peroxidase release MPO that converts hydralazine into a cytotoxic product that is immunogenic for T cells that activate ANCA-producing B cells.
4. Histone H3 trimethyl Lys27 (H3K27me3) levels are perturbed in HIAV, which leads to aberrant gene silencing of proteinase 3 and MPO.In contrast, the demethylase Jumonji domain-containing protein 3 for the H3K27me3 histone is increased in patients without HIAV. Based on this data and the data showing a role for hydralazine in reversing epigenetic silencing of tumor suppressor genes in cancer cells,¹³ it has been proposed that hydralazine may reverse epigenetic silencing of proteinase 3 and MPO.

Diagnosing HIAV is still difficult because physicians do not recognize the drug as the etiologic agent, there is extensive variability in duration between starting the drug and onset of symptoms, and there often is a failure to order the appropriate laboratory and invasive tests needed for evaluation and diagnosis.^3,5,8,10,12 Despite these difficulties, a set of criteria and practices for diagnosis are delineated in Table 1, with the key diagnostic feature being resolution with hydralazine cessation.^1,5,7,8,12

Laboratory test results including serum MPO-ANCA (perinuclear ANCA) with coexisting elastase and/or lactoferrin autoantibodies is characteristic of HIAV. Antinuclear antibody, antihistone, anti–double-stranded DNA, and antiphospholipid antibodies along with low complement levels also may be present.^{2,4,9,10,13,15} It is recommended that ANCA assays combine indirect immunofluorescence with antigen-specific enzyme-linked immunosorbent assay.⁸ With respect to its idiopathic counterpart, patients may only present with MPO-ANCA, while other aforementioned antibodies (eg, antihistone, anti–double-stranded DNA) are rarely found or are entirely absent.^2,9 Patients with HIAV often have higher titers of MPO-ANCA.^9,15 In hydralazine-induced lupus, patients rarely have MPO-ANCA.

When a diagnosis of HIAV is made, it cannot be confirmed until hydralazine is discontinued and the patient’s symptoms resolve. Therefore, it is both diagnostic and therapeutic to discontinue hydralazine when HIAV is suspected. If recognized when the patient is only presenting with nonspecific symptoms, simple hydralazine cessation may be all that is needed; however, because recognition and diagnosis of HIAV is difficult, most patients present when the disease is severe and has progressed to organ involvement.^8-10

Treatment recommendations are highlighted in Table 2.^8,9,12 Glucocorticoid therapy is believed to work by preventing T-cell and B-cell maturation needed to produce MPO-ANCA. Rituximab, on the other hand, is suspected to act by clearing the peripheral blood of MPO-ANCA B cells.^12,16 Of note, patients with HIAV are different from their idiopathic counterparts because they usually need shorter courses of immunosuppressive therapy, long-term maintenance usually is unnecessary, and their prognosis generally is good if the offending agent is withdrawn.^7-9,12 Once the appropriate therapy is instituted, vasculitic manifestations are expected to resolve 10 days to 8 months after hydralazine cessation; however, a response often is seen within 1 to 4 weeks after initiation of systemic treatment.^4,8 Serum ANCA should be monitored, and there should be surveillance for the emergence of a chronic underlying vasculitis.^8,12

To the Editor:

Hydralazine-induced antineutrophil cytoplasmic antibody vasculitis (HIAV) is a rare side effect that may develop in patients treated with hydralazine. Without early recognition and hydralazine cessation, patients often develop acute renal failure and pulmonary hemorrhage that may result in death. We present a case of HIAV.

A 67-year-old woman presented with progressive, tense, hemorrhagic, and necrotic bullae on both sides of the face and neck as well as the extremities of 2 weeks’ duration. She had a history of hypertension and a thyroid nodule after unilateral thyroid lobectomy. A review of symptoms was positive for worsening dyspnea and progressive generalized weakness. Noteworthy medications included amlodipine, metoprolol, levothyroxine, and oral hydralazine 75 mg 3 times daily for 13 months.

Bullae first appeared on the patient’s scalp and quickly progressed with a cephalocaudal pattern with a propensity for the eyes, nostrils, and labial mucosa (Figure 1). The tongue was covered by an eschar, and she had diffuse periorbital edema. Additionally, concentric purpuric patches were noted on the thighs and lower legs (Figure 2).

While hospitalized, she developed pulmonary hemorrhages and a progressive decline in respiratory status. She subsequently was admitted to the medical intensive care unit. Aggressive support was administered, and several skin biopsy specimens were obtained along with an endobronchial biopsy of the right middle lobe.

Skin histopathology revealed a necrotic vasculitis (Figure 3). Direct immunofluorescence was not performed. Lung histopathology showed fragments of bronchial tissue with acute and chronic inflammation, focal necrosis, granulation tissue formation, edema, and squamous metaplasia. Together with the clinical history, these findings were consistent with HIAV.

Hydralazine was first introduced in 1951 for adjunctive hypertension therapy due to its vasodilation effects.^1-3 Since its introduction, it has been implicated in 2 important disease processes: HIAV and hydralazine-induced lupus.

Hydralazine-induced ANCA vasculitis was first documented in 1980; by 2011, multiple cases had been reported.^1-7 Hydralazine-induced ANCA vasculitis has occurred in patients aged 11 to 79 years taking 50 to 300 mg daily. Symptom onset varies from 6 months to 14 years, with a mean exposure duration of 4.7 years and mean daily dose of 142 mg.^1-7

Clinical manifestations range from less specific, such as fever, malaise, arthralgia, myalgia, and weight loss, to single tissue or organ involvement that may be fatal. The most frequent clinical features include kidney involvement (81%), cutaneous vasculitis (25%), arthralgia (24%), and pleuropulmonary involvement (19%). Cutaneous manifestations include but are not limited to palpable lower extremity purpura; morbilliform eruptions; and hemorrhagic blisters on the lower legs, arms, trunk, nasal septum, and uvula.^1-4,8

The most commonly affected organ is the kidney, which commonly presents as hematuria, proteinuria, and elevated serum creatinine level. Histopathologically, patients most likely will have necrotizing and crescentic glomerulonephritis that is pauci-immune by immunofluorescence.^7,9 The lungs are the next most commonly affected organ, with a classic presentation of cough, dyspnea, and hemoptysis in the setting of intra-alveolar hemorrhage.^6,8 When both the kidneys and lungs are involved, the patient is said to have pulmonary-renal syndrome that is characterized by lung infiltrates or nodules with or without hemorrhage, hemoptysis, and pleuritis in the setting of glomerulonephritis.^1,6

Clear data on incidence and prevalence of HIAV does not exist due to the rarity of the disease and the lack of prospective studies. To identify a clear incidence and prevalence, prospective longitudinal studies with larger cohorts along with better recognition and diagnosis are needed.^2,8,10 A few predisposing risk factors have been identified, including older age, a cumulative dose of 100 g at the time of presentation, female sex, a history of thyroid disease, HLA-DR4 genotypes, slow hepatic acetylation, and the null gene for C4.^1,3,5,9-11 Our patient was an older woman with a history of thyroid disease who had been taking oral hydralazine 75 mg 3 times daily for 13 months. During this 13-month duration, she had no dose adjustments.

Currently, the pathomechanism for HIAV is unclear and may be multifactorial. There are 4 main theories^2,8-10,12,13:

1. Hydralazine and its metabolites accumulate inside neutrophils, then subsequently bind and alter the configuration of myeloperoxidase (MPO). This alteration leads to spreading of the autoimmune response to other autoantigens, making neutrophil proteins (eg, elastase, lactoferrin, nuclear antigens) immunogenic.
2. Hydralazine binds MPO in neutrophils, creating cytotoxic products that induce neutrophil apoptosis. Neutrophil apoptosis without priming then results in ANCA antigen presence on the neutrophil cell membrane and the formation of MPO-ANCA. Myeloperoxidase-ANCA then binds to these membrane-bound antigens that cause self-perpetuating, constitutive activation through cross-linking with proteinase 3 or MPO and Fcγ receptors.
3. Activated neutrophils in the presence of hydrogen peroxidase release MPO that converts hydralazine into a cytotoxic product that is immunogenic for T cells that activate ANCA-producing B cells.
4. Histone H3 trimethyl Lys27 (H3K27me3) levels are perturbed in HIAV, which leads to aberrant gene silencing of proteinase 3 and MPO.In contrast, the demethylase Jumonji domain-containing protein 3 for the H3K27me3 histone is increased in patients without HIAV. Based on this data and the data showing a role for hydralazine in reversing epigenetic silencing of tumor suppressor genes in cancer cells,¹³ it has been proposed that hydralazine may reverse epigenetic silencing of proteinase 3 and MPO.

Diagnosing HIAV is still difficult because physicians do not recognize the drug as the etiologic agent, there is extensive variability in duration between starting the drug and onset of symptoms, and there often is a failure to order the appropriate laboratory and invasive tests needed for evaluation and diagnosis.^3,5,8,10,12 Despite these difficulties, a set of criteria and practices for diagnosis are delineated in Table 1, with the key diagnostic feature being resolution with hydralazine cessation.^1,5,7,8,12

Laboratory test results including serum MPO-ANCA (perinuclear ANCA) with coexisting elastase and/or lactoferrin autoantibodies is characteristic of HIAV. Antinuclear antibody, antihistone, anti–double-stranded DNA, and antiphospholipid antibodies along with low complement levels also may be present.^{2,4,9,10,13,15} It is recommended that ANCA assays combine indirect immunofluorescence with antigen-specific enzyme-linked immunosorbent assay.⁸ With respect to its idiopathic counterpart, patients may only present with MPO-ANCA, while other aforementioned antibodies (eg, antihistone, anti–double-stranded DNA) are rarely found or are entirely absent.^2,9 Patients with HIAV often have higher titers of MPO-ANCA.^9,15 In hydralazine-induced lupus, patients rarely have MPO-ANCA.

When a diagnosis of HIAV is made, it cannot be confirmed until hydralazine is discontinued and the patient’s symptoms resolve. Therefore, it is both diagnostic and therapeutic to discontinue hydralazine when HIAV is suspected. If recognized when the patient is only presenting with nonspecific symptoms, simple hydralazine cessation may be all that is needed; however, because recognition and diagnosis of HIAV is difficult, most patients present when the disease is severe and has progressed to organ involvement.^8-10

Treatment recommendations are highlighted in Table 2.^8,9,12 Glucocorticoid therapy is believed to work by preventing T-cell and B-cell maturation needed to produce MPO-ANCA. Rituximab, on the other hand, is suspected to act by clearing the peripheral blood of MPO-ANCA B cells.^12,16 Of note, patients with HIAV are different from their idiopathic counterparts because they usually need shorter courses of immunosuppressive therapy, long-term maintenance usually is unnecessary, and their prognosis generally is good if the offending agent is withdrawn.^7-9,12 Once the appropriate therapy is instituted, vasculitic manifestations are expected to resolve 10 days to 8 months after hydralazine cessation; however, a response often is seen within 1 to 4 weeks after initiation of systemic treatment.^4,8 Serum ANCA should be monitored, and there should be surveillance for the emergence of a chronic underlying vasculitis.^8,12

To the Editor:

Hydralazine-induced antineutrophil cytoplasmic antibody vasculitis (HIAV) is a rare side effect that may develop in patients treated with hydralazine. Without early recognition and hydralazine cessation, patients often develop acute renal failure and pulmonary hemorrhage that may result in death. We present a case of HIAV.

A 67-year-old woman presented with progressive, tense, hemorrhagic, and necrotic bullae on both sides of the face and neck as well as the extremities of 2 weeks’ duration. She had a history of hypertension and a thyroid nodule after unilateral thyroid lobectomy. A review of symptoms was positive for worsening dyspnea and progressive generalized weakness. Noteworthy medications included amlodipine, metoprolol, levothyroxine, and oral hydralazine 75 mg 3 times daily for 13 months.

Bullae first appeared on the patient’s scalp and quickly progressed with a cephalocaudal pattern with a propensity for the eyes, nostrils, and labial mucosa (Figure 1). The tongue was covered by an eschar, and she had diffuse periorbital edema. Additionally, concentric purpuric patches were noted on the thighs and lower legs (Figure 2).

While hospitalized, she developed pulmonary hemorrhages and a progressive decline in respiratory status. She subsequently was admitted to the medical intensive care unit. Aggressive support was administered, and several skin biopsy specimens were obtained along with an endobronchial biopsy of the right middle lobe.

Skin histopathology revealed a necrotic vasculitis (Figure 3). Direct immunofluorescence was not performed. Lung histopathology showed fragments of bronchial tissue with acute and chronic inflammation, focal necrosis, granulation tissue formation, edema, and squamous metaplasia. Together with the clinical history, these findings were consistent with HIAV.

Hydralazine was first introduced in 1951 for adjunctive hypertension therapy due to its vasodilation effects.^1-3 Since its introduction, it has been implicated in 2 important disease processes: HIAV and hydralazine-induced lupus.

Hydralazine-induced ANCA vasculitis was first documented in 1980; by 2011, multiple cases had been reported.^1-7 Hydralazine-induced ANCA vasculitis has occurred in patients aged 11 to 79 years taking 50 to 300 mg daily. Symptom onset varies from 6 months to 14 years, with a mean exposure duration of 4.7 years and mean daily dose of 142 mg.^1-7

Clinical manifestations range from less specific, such as fever, malaise, arthralgia, myalgia, and weight loss, to single tissue or organ involvement that may be fatal. The most frequent clinical features include kidney involvement (81%), cutaneous vasculitis (25%), arthralgia (24%), and pleuropulmonary involvement (19%). Cutaneous manifestations include but are not limited to palpable lower extremity purpura; morbilliform eruptions; and hemorrhagic blisters on the lower legs, arms, trunk, nasal septum, and uvula.^1-4,8

The most commonly affected organ is the kidney, which commonly presents as hematuria, proteinuria, and elevated serum creatinine level. Histopathologically, patients most likely will have necrotizing and crescentic glomerulonephritis that is pauci-immune by immunofluorescence.^7,9 The lungs are the next most commonly affected organ, with a classic presentation of cough, dyspnea, and hemoptysis in the setting of intra-alveolar hemorrhage.^6,8 When both the kidneys and lungs are involved, the patient is said to have pulmonary-renal syndrome that is characterized by lung infiltrates or nodules with or without hemorrhage, hemoptysis, and pleuritis in the setting of glomerulonephritis.^1,6

Clear data on incidence and prevalence of HIAV does not exist due to the rarity of the disease and the lack of prospective studies. To identify a clear incidence and prevalence, prospective longitudinal studies with larger cohorts along with better recognition and diagnosis are needed.^2,8,10 A few predisposing risk factors have been identified, including older age, a cumulative dose of 100 g at the time of presentation, female sex, a history of thyroid disease, HLA-DR4 genotypes, slow hepatic acetylation, and the null gene for C4.^1,3,5,9-11 Our patient was an older woman with a history of thyroid disease who had been taking oral hydralazine 75 mg 3 times daily for 13 months. During this 13-month duration, she had no dose adjustments.

Currently, the pathomechanism for HIAV is unclear and may be multifactorial. There are 4 main theories^2,8-10,12,13:

1. Hydralazine and its metabolites accumulate inside neutrophils, then subsequently bind and alter the configuration of myeloperoxidase (MPO). This alteration leads to spreading of the autoimmune response to other autoantigens, making neutrophil proteins (eg, elastase, lactoferrin, nuclear antigens) immunogenic.
2. Hydralazine binds MPO in neutrophils, creating cytotoxic products that induce neutrophil apoptosis. Neutrophil apoptosis without priming then results in ANCA antigen presence on the neutrophil cell membrane and the formation of MPO-ANCA. Myeloperoxidase-ANCA then binds to these membrane-bound antigens that cause self-perpetuating, constitutive activation through cross-linking with proteinase 3 or MPO and Fcγ receptors.
3. Activated neutrophils in the presence of hydrogen peroxidase release MPO that converts hydralazine into a cytotoxic product that is immunogenic for T cells that activate ANCA-producing B cells.
4. Histone H3 trimethyl Lys27 (H3K27me3) levels are perturbed in HIAV, which leads to aberrant gene silencing of proteinase 3 and MPO.In contrast, the demethylase Jumonji domain-containing protein 3 for the H3K27me3 histone is increased in patients without HIAV. Based on this data and the data showing a role for hydralazine in reversing epigenetic silencing of tumor suppressor genes in cancer cells,¹³ it has been proposed that hydralazine may reverse epigenetic silencing of proteinase 3 and MPO.

Diagnosing HIAV is still difficult because physicians do not recognize the drug as the etiologic agent, there is extensive variability in duration between starting the drug and onset of symptoms, and there often is a failure to order the appropriate laboratory and invasive tests needed for evaluation and diagnosis.^3,5,8,10,12 Despite these difficulties, a set of criteria and practices for diagnosis are delineated in Table 1, with the key diagnostic feature being resolution with hydralazine cessation.^1,5,7,8,12

Laboratory test results including serum MPO-ANCA (perinuclear ANCA) with coexisting elastase and/or lactoferrin autoantibodies is characteristic of HIAV. Antinuclear antibody, antihistone, anti–double-stranded DNA, and antiphospholipid antibodies along with low complement levels also may be present.^{2,4,9,10,13,15} It is recommended that ANCA assays combine indirect immunofluorescence with antigen-specific enzyme-linked immunosorbent assay.⁸ With respect to its idiopathic counterpart, patients may only present with MPO-ANCA, while other aforementioned antibodies (eg, antihistone, anti–double-stranded DNA) are rarely found or are entirely absent.^2,9 Patients with HIAV often have higher titers of MPO-ANCA.^9,15 In hydralazine-induced lupus, patients rarely have MPO-ANCA.

When a diagnosis of HIAV is made, it cannot be confirmed until hydralazine is discontinued and the patient’s symptoms resolve. Therefore, it is both diagnostic and therapeutic to discontinue hydralazine when HIAV is suspected. If recognized when the patient is only presenting with nonspecific symptoms, simple hydralazine cessation may be all that is needed; however, because recognition and diagnosis of HIAV is difficult, most patients present when the disease is severe and has progressed to organ involvement.^8-10

Treatment recommendations are highlighted in Table 2.^8,9,12 Glucocorticoid therapy is believed to work by preventing T-cell and B-cell maturation needed to produce MPO-ANCA. Rituximab, on the other hand, is suspected to act by clearing the peripheral blood of MPO-ANCA B cells.^12,16 Of note, patients with HIAV are different from their idiopathic counterparts because they usually need shorter courses of immunosuppressive therapy, long-term maintenance usually is unnecessary, and their prognosis generally is good if the offending agent is withdrawn.^7-9,12 Once the appropriate therapy is instituted, vasculitic manifestations are expected to resolve 10 days to 8 months after hydralazine cessation; however, a response often is seen within 1 to 4 weeks after initiation of systemic treatment.^4,8 Serum ANCA should be monitored, and there should be surveillance for the emergence of a chronic underlying vasculitis.^8,12

ANSWER

The correct answer is psoriasis vulgaris (choice “a”).

DISCUSSION

At least 30% of patients with psoriasis have a family history of the disease—a meaningful clue in developing a differential. Besides asking about the history, always look for corroborating signs in areas where the disease is commonly seen (eg, the fingernails). In this case, further corroboration was provided by the history of illness at the time of the rash’s onset; what was initially strep-driven guttate psoriasis morphed into full-blown psoriasis vulgaris.

The heavy scales, with their salmon-pink base, tipped the scales in favor of psoriasis as the diagnosis. The pinpoint bleeding (known as the Auspitz sign), although not pathognomic for psoriasis, is certainly suggestive of it.

In adults, these findings would probably have been sufficient to settle on psoriasis. But before labeling a young child with a serious, lifelong diagnosis, it was necessary to be sure. For one thing, advanced psoriasis is very unusual in children as young as this patient, and for another, treatment would likely be problematic. Fortunately for clarity’s sake, the biopsy was consistent with psoriasis and inconsistent with the other items in the differential.

TREATMENT

The patient was prescribed a topical steroid cream to apply every other day, alternating with vitamin D–derived ointment. In addition, he was advised to increase his exposure to natural sunlight. Phototherapy with narrow-band ultraviolet light B would be a superior option, but his family lives too far from the clinic to make 3 roundtrips per week for such treatment.

If these measures fail, a biologic agent may be appropriate. Unfortunately, the patient’s insurance carrier requires the failure of several other modalities before it will approve use of such therapy.

ANSWER

The correct answer is psoriasis vulgaris (choice “a”).

DISCUSSION

At least 30% of patients with psoriasis have a family history of the disease—a meaningful clue in developing a differential. Besides asking about the history, always look for corroborating signs in areas where the disease is commonly seen (eg, the fingernails). In this case, further corroboration was provided by the history of illness at the time of the rash’s onset; what was initially strep-driven guttate psoriasis morphed into full-blown psoriasis vulgaris.

The heavy scales, with their salmon-pink base, tipped the scales in favor of psoriasis as the diagnosis. The pinpoint bleeding (known as the Auspitz sign), although not pathognomic for psoriasis, is certainly suggestive of it.

In adults, these findings would probably have been sufficient to settle on psoriasis. But before labeling a young child with a serious, lifelong diagnosis, it was necessary to be sure. For one thing, advanced psoriasis is very unusual in children as young as this patient, and for another, treatment would likely be problematic. Fortunately for clarity’s sake, the biopsy was consistent with psoriasis and inconsistent with the other items in the differential.

TREATMENT

The patient was prescribed a topical steroid cream to apply every other day, alternating with vitamin D–derived ointment. In addition, he was advised to increase his exposure to natural sunlight. Phototherapy with narrow-band ultraviolet light B would be a superior option, but his family lives too far from the clinic to make 3 roundtrips per week for such treatment.

If these measures fail, a biologic agent may be appropriate. Unfortunately, the patient’s insurance carrier requires the failure of several other modalities before it will approve use of such therapy.

ANSWER

The correct answer is psoriasis vulgaris (choice “a”).

DISCUSSION

At least 30% of patients with psoriasis have a family history of the disease—a meaningful clue in developing a differential. Besides asking about the history, always look for corroborating signs in areas where the disease is commonly seen (eg, the fingernails). In this case, further corroboration was provided by the history of illness at the time of the rash’s onset; what was initially strep-driven guttate psoriasis morphed into full-blown psoriasis vulgaris.

The heavy scales, with their salmon-pink base, tipped the scales in favor of psoriasis as the diagnosis. The pinpoint bleeding (known as the Auspitz sign), although not pathognomic for psoriasis, is certainly suggestive of it.

In adults, these findings would probably have been sufficient to settle on psoriasis. But before labeling a young child with a serious, lifelong diagnosis, it was necessary to be sure. For one thing, advanced psoriasis is very unusual in children as young as this patient, and for another, treatment would likely be problematic. Fortunately for clarity’s sake, the biopsy was consistent with psoriasis and inconsistent with the other items in the differential.

TREATMENT

The patient was prescribed a topical steroid cream to apply every other day, alternating with vitamin D–derived ointment. In addition, he was advised to increase his exposure to natural sunlight. Phototherapy with narrow-band ultraviolet light B would be a superior option, but his family lives too far from the clinic to make 3 roundtrips per week for such treatment.

If these measures fail, a biologic agent may be appropriate. Unfortunately, the patient’s insurance carrier requires the failure of several other modalities before it will approve use of such therapy.

NEW ORLEANS – Weight-based harassment and bias is extremely prevalent throughout society and in doctors’ own offices, so be aware of ways to address it and support your patients regardless of weight.

Rebecca Puhl, PhD, a deputy director of the Rudd Center for Food Policy and Obesity at the University of Connecticut, Hartford, said that weight-based discrimination can occur whatever a person’s size or body shape, but it’s most often targeted at youth who are overweight or obese.

These children and teens commonly face teasing, harassment, cyberbullying, physical aggression, and social bullying from peers, coaches, teachers, and even parents, Dr. Puhl told attendees at the annual meeting of the American Academy of Pediatrics.

Common beliefs about overweight people – that they have little self discipline or poor eating and activity habits – only perpetuate stereotypes, she said. Common stereotypes are that people with obesity are noncompliant, lazy, sloppy, unsuccessful, unintelligent, dishonest, and awkward.

And health professionals of every type have been found to harbor these biases. In one study of more than 4,000 first-year medical students, well over half the respondents revealed explicit (74%) and implicit (67%) weight bias (Obesity. 2014 Apr;22[4]:1201-8). The study also found that explicit weight bias was stronger than explicit bias against blacks, Hispanics, LGBTQ people, and poor people.
 

Know the effects of weight stigma

Far from a minor issue, the discrimination that begins in childhood against those who are overweight can have a long-lasting impact on their future prospects and mental health. Being overweight is overwhelmingly cited as the most common reason for bullying (Pediatr Obes. 2016 Aug;11[4]:241-50). Dr. Puhl described to attendees how weight bias shifts throughout a lifetime, beginning as early as preschool. In childhood, the stereotypes about being overweight worsen, and the teasing and bullying increase. By adolescence, this treatment affects teens’ psychological, social, and physical well-being. It then translates in adulthood into reduced opportunities in employment and education, and poorer access and treatment in health care.

The mental distress caused by weight bullying often takes the form of depression, anxiety, and substance use, Dr. Puhl said, and children’s academic success can be hampered by bullying about their weight. One study found a higher risk of poor grades and school avoidance with each additional teasing incident (J Youth Adolesc. 2012 Jan;41[1]:27-40).

Weight stigma also can contribute to more weight gain, obesity, and lower physical activity levels. Maladaptive eating behaviors can result from weight stigmatization as well: binge eating, emotional eating, increased consumption in general, and other eating disorders. Severe binge eating is 80% more likely among teens who are bullied about their weight, Dr. Puhl said, and the risk increases with increased frequency and types of bullying.

Children who are teased about their weight often become less willing to engage in physical activity, she noted. They may skip gym class, feel less competent about physical activity, and end up enjoying sports participation less.

Further, sexual- and gender-minority youth report high rates of weight-related teasing from friends and family regardless of their body mass index (BMI) percentile, Dr. Puhl emphasized. Researchers have found bullying about weight in this population linked to dieting, difficulty sleeping, high stress levels, binge drinking, smoking, and marijuana use.
 

Know how to combat weight bias

Dr. Puhl described strategies for reducing weight bias based on clinical practice recommendations in the American Academy of Pediatrics’ policy statement entitled “Stigma Experienced by Children and Adolescents With Obesity” (Pediatrics. 2017 Dec;140[6]:e20173034).

Be aware. Consider how personal assumptions and attitudes about weight can affect your body language, tone of voice, facial expression, gestures, eye contact (or lack thereof), and spatial distance from the patient.

Recognizing the biological, genetic, and environmental causes of obesity can reduce stigma and improve understanding of the complexity of obesity etiology. It’s also important that you help parents understand this complexity and the negative impact of weight stigma.

Consider language and word choice. “Carefully consider language that might unintentionally communicate bias, blame, or negative judgment,” Dr. Puhl told attendees. “Use language that is supportive and empowering.”

Terms such as “unhealthy weight” and “high BMI” are less stigmatizing than “fat” and “morbidly obese” to parents, she said, and research has found nearly a quarter of parents would avoid future doctor appointments if their child’s doctor used stigmatizing terms to discuss weight (Pediatrics. 2011 Oct;128[4]:e786-93).

Teens themselves may have diverse preferences for the language used. Start by asking: “Could we talk about your weight today?” and then follow up by directly asking, “what words would you feel most comfortable with as we talk about your weight?”

Person-first language – such as “person with obesity” instead of “obese person” also is important to reducing stigma, she said.

It’s normal for you to feel uneasy about bringing up weight with patients, so Dr. Puhl recommended you practice dialogue out loud.

“Acknowledge your strengths,” she said. “You already have the skills and experience of engaging in difficult conversations with patients and families on a range of other health issues,” so apply that in this context as well.

Screen for negative experiences that could indicate weight-based bullying. These could include teasing and bullying, low self-esteem, poor school performance, depression, and anxiety.

“Remember that weight-based victimization can occur at diverse body sizes, not just in youth with obesity,” Dr. Puhl said. If you discover your patient is experiencing weight-related bullying, determine whether they have a support system in place and whether a mental health referral is appropriate. Provide or refer for behavior change counseling with motivational interviewing and patient-centered, empathic approaches. Parents should be aware of the issue and should contact the child’s teachers and school administration to help address it.

But before you do that, keep in mind that it’s not just peers doing the bullying. According to a study of teens with obesity enrolled in a national weight-loss camp, 37% of teen participants in 2012 said that their parents bully them (Pediatrics. 2013 Jan;131[1]:e1-9).

You should assess whether family interactions or the parents’ own history with weight is involved. If parents make disparaging comments about their child’s weight, “use this as an opportunity to model appropriate language and educate parents about weight bias,” Dr. Puhl said.

It’s also important to realize that parents themselves often are frustrated, so critical comments about their language or approach can backfire, she warned. Instead, help parents understand how to create a home setting that encourages healthy food choices, praises children for healthy decision making, and models positive health behaviors. It is key for them to focus on improving their children’s health behaviors rather than focusing on weight.

And before you contact the school, remember teachers also are common perpetrators of weight stigma, Dr. Puhl noted. She gave as an example a study in which investigators assessed 133 teachers’ perceptions of middle or high school students’ abilities based on photos that had been digitally altered to show each girl both as average weight or as overweight. Each photo was associated with an essay specifically chosen because it was neither particularly good nor bad (Brit J Educ Psychol. 2019 Oct 26. doi: 10.1111/bjep.12322). The teachers judged the essays believed to be submitted by overweight girls to be “similar in structural quality,” but they gave the overweight girls lower grades than the average-weight girls. They also indicated that they considered the overweight girls “put forth more effort, needed more remedial assistance, and had lower overall grades in school.” The teachers also rated other teachers’ weight bias to be at a low level, and their own weight bias to be “significantly lower” than the others.

Assess your clinical environment. Be aware of your clinical environment and whether it meets the needs of youth with diverse body sizes. That includes having a range of sturdy armless seating options and adequately sized doorways, hallways, and restrooms. You also should have beds, wheelchairs, and exam tables with adequate weight capacity. Also check that you have supplies, such as robes or blood pressure cuffs, on hand for a variety of body sizes.

NEW ORLEANS – Weight-based harassment and bias is extremely prevalent throughout society and in doctors’ own offices, so be aware of ways to address it and support your patients regardless of weight.

Rebecca Puhl, PhD, a deputy director of the Rudd Center for Food Policy and Obesity at the University of Connecticut, Hartford, said that weight-based discrimination can occur whatever a person’s size or body shape, but it’s most often targeted at youth who are overweight or obese.

These children and teens commonly face teasing, harassment, cyberbullying, physical aggression, and social bullying from peers, coaches, teachers, and even parents, Dr. Puhl told attendees at the annual meeting of the American Academy of Pediatrics.

Common beliefs about overweight people – that they have little self discipline or poor eating and activity habits – only perpetuate stereotypes, she said. Common stereotypes are that people with obesity are noncompliant, lazy, sloppy, unsuccessful, unintelligent, dishonest, and awkward.

And health professionals of every type have been found to harbor these biases. In one study of more than 4,000 first-year medical students, well over half the respondents revealed explicit (74%) and implicit (67%) weight bias (Obesity. 2014 Apr;22[4]:1201-8). The study also found that explicit weight bias was stronger than explicit bias against blacks, Hispanics, LGBTQ people, and poor people.
 

Know the effects of weight stigma

Far from a minor issue, the discrimination that begins in childhood against those who are overweight can have a long-lasting impact on their future prospects and mental health. Being overweight is overwhelmingly cited as the most common reason for bullying (Pediatr Obes. 2016 Aug;11[4]:241-50). Dr. Puhl described to attendees how weight bias shifts throughout a lifetime, beginning as early as preschool. In childhood, the stereotypes about being overweight worsen, and the teasing and bullying increase. By adolescence, this treatment affects teens’ psychological, social, and physical well-being. It then translates in adulthood into reduced opportunities in employment and education, and poorer access and treatment in health care.

The mental distress caused by weight bullying often takes the form of depression, anxiety, and substance use, Dr. Puhl said, and children’s academic success can be hampered by bullying about their weight. One study found a higher risk of poor grades and school avoidance with each additional teasing incident (J Youth Adolesc. 2012 Jan;41[1]:27-40).

Weight stigma also can contribute to more weight gain, obesity, and lower physical activity levels. Maladaptive eating behaviors can result from weight stigmatization as well: binge eating, emotional eating, increased consumption in general, and other eating disorders. Severe binge eating is 80% more likely among teens who are bullied about their weight, Dr. Puhl said, and the risk increases with increased frequency and types of bullying.

Children who are teased about their weight often become less willing to engage in physical activity, she noted. They may skip gym class, feel less competent about physical activity, and end up enjoying sports participation less.

Further, sexual- and gender-minority youth report high rates of weight-related teasing from friends and family regardless of their body mass index (BMI) percentile, Dr. Puhl emphasized. Researchers have found bullying about weight in this population linked to dieting, difficulty sleeping, high stress levels, binge drinking, smoking, and marijuana use.
 

Know how to combat weight bias

Dr. Puhl described strategies for reducing weight bias based on clinical practice recommendations in the American Academy of Pediatrics’ policy statement entitled “Stigma Experienced by Children and Adolescents With Obesity” (Pediatrics. 2017 Dec;140[6]:e20173034).

Be aware. Consider how personal assumptions and attitudes about weight can affect your body language, tone of voice, facial expression, gestures, eye contact (or lack thereof), and spatial distance from the patient.

Recognizing the biological, genetic, and environmental causes of obesity can reduce stigma and improve understanding of the complexity of obesity etiology. It’s also important that you help parents understand this complexity and the negative impact of weight stigma.

Consider language and word choice. “Carefully consider language that might unintentionally communicate bias, blame, or negative judgment,” Dr. Puhl told attendees. “Use language that is supportive and empowering.”

Terms such as “unhealthy weight” and “high BMI” are less stigmatizing than “fat” and “morbidly obese” to parents, she said, and research has found nearly a quarter of parents would avoid future doctor appointments if their child’s doctor used stigmatizing terms to discuss weight (Pediatrics. 2011 Oct;128[4]:e786-93).

Teens themselves may have diverse preferences for the language used. Start by asking: “Could we talk about your weight today?” and then follow up by directly asking, “what words would you feel most comfortable with as we talk about your weight?”

Person-first language – such as “person with obesity” instead of “obese person” also is important to reducing stigma, she said.

It’s normal for you to feel uneasy about bringing up weight with patients, so Dr. Puhl recommended you practice dialogue out loud.

“Acknowledge your strengths,” she said. “You already have the skills and experience of engaging in difficult conversations with patients and families on a range of other health issues,” so apply that in this context as well.

Screen for negative experiences that could indicate weight-based bullying. These could include teasing and bullying, low self-esteem, poor school performance, depression, and anxiety.

“Remember that weight-based victimization can occur at diverse body sizes, not just in youth with obesity,” Dr. Puhl said. If you discover your patient is experiencing weight-related bullying, determine whether they have a support system in place and whether a mental health referral is appropriate. Provide or refer for behavior change counseling with motivational interviewing and patient-centered, empathic approaches. Parents should be aware of the issue and should contact the child’s teachers and school administration to help address it.

But before you do that, keep in mind that it’s not just peers doing the bullying. According to a study of teens with obesity enrolled in a national weight-loss camp, 37% of teen participants in 2012 said that their parents bully them (Pediatrics. 2013 Jan;131[1]:e1-9).

You should assess whether family interactions or the parents’ own history with weight is involved. If parents make disparaging comments about their child’s weight, “use this as an opportunity to model appropriate language and educate parents about weight bias,” Dr. Puhl said.

It’s also important to realize that parents themselves often are frustrated, so critical comments about their language or approach can backfire, she warned. Instead, help parents understand how to create a home setting that encourages healthy food choices, praises children for healthy decision making, and models positive health behaviors. It is key for them to focus on improving their children’s health behaviors rather than focusing on weight.

And before you contact the school, remember teachers also are common perpetrators of weight stigma, Dr. Puhl noted. She gave as an example a study in which investigators assessed 133 teachers’ perceptions of middle or high school students’ abilities based on photos that had been digitally altered to show each girl both as average weight or as overweight. Each photo was associated with an essay specifically chosen because it was neither particularly good nor bad (Brit J Educ Psychol. 2019 Oct 26. doi: 10.1111/bjep.12322). The teachers judged the essays believed to be submitted by overweight girls to be “similar in structural quality,” but they gave the overweight girls lower grades than the average-weight girls. They also indicated that they considered the overweight girls “put forth more effort, needed more remedial assistance, and had lower overall grades in school.” The teachers also rated other teachers’ weight bias to be at a low level, and their own weight bias to be “significantly lower” than the others.

Assess your clinical environment. Be aware of your clinical environment and whether it meets the needs of youth with diverse body sizes. That includes having a range of sturdy armless seating options and adequately sized doorways, hallways, and restrooms. You also should have beds, wheelchairs, and exam tables with adequate weight capacity. Also check that you have supplies, such as robes or blood pressure cuffs, on hand for a variety of body sizes.

NEW ORLEANS – Weight-based harassment and bias is extremely prevalent throughout society and in doctors’ own offices, so be aware of ways to address it and support your patients regardless of weight.

Rebecca Puhl, PhD, a deputy director of the Rudd Center for Food Policy and Obesity at the University of Connecticut, Hartford, said that weight-based discrimination can occur whatever a person’s size or body shape, but it’s most often targeted at youth who are overweight or obese.

These children and teens commonly face teasing, harassment, cyberbullying, physical aggression, and social bullying from peers, coaches, teachers, and even parents, Dr. Puhl told attendees at the annual meeting of the American Academy of Pediatrics.

Common beliefs about overweight people – that they have little self discipline or poor eating and activity habits – only perpetuate stereotypes, she said. Common stereotypes are that people with obesity are noncompliant, lazy, sloppy, unsuccessful, unintelligent, dishonest, and awkward.

And health professionals of every type have been found to harbor these biases. In one study of more than 4,000 first-year medical students, well over half the respondents revealed explicit (74%) and implicit (67%) weight bias (Obesity. 2014 Apr;22[4]:1201-8). The study also found that explicit weight bias was stronger than explicit bias against blacks, Hispanics, LGBTQ people, and poor people.
 

Know the effects of weight stigma

Far from a minor issue, the discrimination that begins in childhood against those who are overweight can have a long-lasting impact on their future prospects and mental health. Being overweight is overwhelmingly cited as the most common reason for bullying (Pediatr Obes. 2016 Aug;11[4]:241-50). Dr. Puhl described to attendees how weight bias shifts throughout a lifetime, beginning as early as preschool. In childhood, the stereotypes about being overweight worsen, and the teasing and bullying increase. By adolescence, this treatment affects teens’ psychological, social, and physical well-being. It then translates in adulthood into reduced opportunities in employment and education, and poorer access and treatment in health care.

The mental distress caused by weight bullying often takes the form of depression, anxiety, and substance use, Dr. Puhl said, and children’s academic success can be hampered by bullying about their weight. One study found a higher risk of poor grades and school avoidance with each additional teasing incident (J Youth Adolesc. 2012 Jan;41[1]:27-40).

Weight stigma also can contribute to more weight gain, obesity, and lower physical activity levels. Maladaptive eating behaviors can result from weight stigmatization as well: binge eating, emotional eating, increased consumption in general, and other eating disorders. Severe binge eating is 80% more likely among teens who are bullied about their weight, Dr. Puhl said, and the risk increases with increased frequency and types of bullying.

Children who are teased about their weight often become less willing to engage in physical activity, she noted. They may skip gym class, feel less competent about physical activity, and end up enjoying sports participation less.

Further, sexual- and gender-minority youth report high rates of weight-related teasing from friends and family regardless of their body mass index (BMI) percentile, Dr. Puhl emphasized. Researchers have found bullying about weight in this population linked to dieting, difficulty sleeping, high stress levels, binge drinking, smoking, and marijuana use.
 

Know how to combat weight bias

Dr. Puhl described strategies for reducing weight bias based on clinical practice recommendations in the American Academy of Pediatrics’ policy statement entitled “Stigma Experienced by Children and Adolescents With Obesity” (Pediatrics. 2017 Dec;140[6]:e20173034).

Be aware. Consider how personal assumptions and attitudes about weight can affect your body language, tone of voice, facial expression, gestures, eye contact (or lack thereof), and spatial distance from the patient.

Recognizing the biological, genetic, and environmental causes of obesity can reduce stigma and improve understanding of the complexity of obesity etiology. It’s also important that you help parents understand this complexity and the negative impact of weight stigma.

Consider language and word choice. “Carefully consider language that might unintentionally communicate bias, blame, or negative judgment,” Dr. Puhl told attendees. “Use language that is supportive and empowering.”

Terms such as “unhealthy weight” and “high BMI” are less stigmatizing than “fat” and “morbidly obese” to parents, she said, and research has found nearly a quarter of parents would avoid future doctor appointments if their child’s doctor used stigmatizing terms to discuss weight (Pediatrics. 2011 Oct;128[4]:e786-93).

Teens themselves may have diverse preferences for the language used. Start by asking: “Could we talk about your weight today?” and then follow up by directly asking, “what words would you feel most comfortable with as we talk about your weight?”

Person-first language – such as “person with obesity” instead of “obese person” also is important to reducing stigma, she said.

It’s normal for you to feel uneasy about bringing up weight with patients, so Dr. Puhl recommended you practice dialogue out loud.

“Acknowledge your strengths,” she said. “You already have the skills and experience of engaging in difficult conversations with patients and families on a range of other health issues,” so apply that in this context as well.

Screen for negative experiences that could indicate weight-based bullying. These could include teasing and bullying, low self-esteem, poor school performance, depression, and anxiety.

“Remember that weight-based victimization can occur at diverse body sizes, not just in youth with obesity,” Dr. Puhl said. If you discover your patient is experiencing weight-related bullying, determine whether they have a support system in place and whether a mental health referral is appropriate. Provide or refer for behavior change counseling with motivational interviewing and patient-centered, empathic approaches. Parents should be aware of the issue and should contact the child’s teachers and school administration to help address it.

But before you do that, keep in mind that it’s not just peers doing the bullying. According to a study of teens with obesity enrolled in a national weight-loss camp, 37% of teen participants in 2012 said that their parents bully them (Pediatrics. 2013 Jan;131[1]:e1-9).

You should assess whether family interactions or the parents’ own history with weight is involved. If parents make disparaging comments about their child’s weight, “use this as an opportunity to model appropriate language and educate parents about weight bias,” Dr. Puhl said.

It’s also important to realize that parents themselves often are frustrated, so critical comments about their language or approach can backfire, she warned. Instead, help parents understand how to create a home setting that encourages healthy food choices, praises children for healthy decision making, and models positive health behaviors. It is key for them to focus on improving their children’s health behaviors rather than focusing on weight.

And before you contact the school, remember teachers also are common perpetrators of weight stigma, Dr. Puhl noted. She gave as an example a study in which investigators assessed 133 teachers’ perceptions of middle or high school students’ abilities based on photos that had been digitally altered to show each girl both as average weight or as overweight. Each photo was associated with an essay specifically chosen because it was neither particularly good nor bad (Brit J Educ Psychol. 2019 Oct 26. doi: 10.1111/bjep.12322). The teachers judged the essays believed to be submitted by overweight girls to be “similar in structural quality,” but they gave the overweight girls lower grades than the average-weight girls. They also indicated that they considered the overweight girls “put forth more effort, needed more remedial assistance, and had lower overall grades in school.” The teachers also rated other teachers’ weight bias to be at a low level, and their own weight bias to be “significantly lower” than the others.

Assess your clinical environment. Be aware of your clinical environment and whether it meets the needs of youth with diverse body sizes. That includes having a range of sturdy armless seating options and adequately sized doorways, hallways, and restrooms. You also should have beds, wheelchairs, and exam tables with adequate weight capacity. Also check that you have supplies, such as robes or blood pressure cuffs, on hand for a variety of body sizes.

CHICAGO – Dual positron emission tomography-computed tomography (PET/CT) scans changed the treatment course of nearly half of patients whose scans were positive for infection. In a single-center systematic review of 18fluorodeoxyglucose (FDG)–PET/CT scans, 55 of the 138 scans (40%) changed clinical management.

Kari Oakes/MDedge News

Presenting the findings at the annual meeting of the Radiological Society of North America, Benjamin Viglianti, MD, PhD, said that PET/CT had particular utility in cases of bacteremia and endocarditis, in which the scans changed treatment in 46% of those cases.

Dr. Viglianti, a radiologist at the University of Michigan, Ann Arbor, explained that medical student and first author Anitha Menon, himself, and their collaborators deliberately used a broad definition of clinical management change. The management course was considered to change not only if an unknown infection site was discovered or if a new intervention was initiated after the scan, but also if antibiotic choice or duration was changed or an additional specialty was consulted.

Scans were included in the study if an infectious etiology was found in the scan and if the patient received an infectious disease consult. Bacteremia and endocarditis were the most frequent indications for scans and also the indications for which management was most frequently changed. When a vascular cause was the indication for the scan, management changed 41% of the time. For fevers of unknown origin, the scan changed management in 30% of the cases, while for osteomyelitis, management was changed for 28% of patients.

The investigators identified several broad themes from their review that pointed toward when clinicians might consider FDG-PET/CT imaging in infectious disease management.

The first, said Dr. Viglianti, was that “for patients with suspected vascular graft infection, PET/CT using FDG may be a good first-choice imaging modality.” He pointed to an illustrative case of a patient who was 1 month out from open repair of a thoracoabdominal aortic aneurysm. The patient had abdominal pain, epigastric tenderness and nausea, as well as an erythematous incision site. A CT scan just revealed an abdominal fluid collection, but the PET/CT scan showed radiotracer uptake at the prior repair site, indicating infection.

For patients with bacteremia, the investigators judged that FDG-PET/CT might be particularly useful in patients who have a graft, prosthetic valve, or cardiac device. Here, Dr. Viglianti and his collaborators highlighted the scan of a woman with DiGeorge syndrome who had received aortic root replacement for truncus arteriosis. She had been found to have persistent enterococcal bacteremia at high levels, but had been symptom free. To take a close look at the suspected infectious nidus, a transesophageal echocardiogram had been obtained, but this study didn’t turn up any clear masses or vegetations. The PET/CT scan, though, revealed avid FDG uptake in the area of the prosthesis.

Management course was not likely to be changed for patients with fever of unknown origin, but the investigators did note that whole-body PET/CT was useful to distinguish infectious etiologies from hematologic and oncologic processes. Their review included a patient who had Crohn’s disease and fever, myalgias, and upper abdominal pain, as well as liver enzyme elevation. The PET/CT showed radiotracer uptake within the spleen, which was enlarged. The scan also showed bone marrow uptake; these findings pointed toward hemophagocytic lymphohistiocytosis rather than an infectious etiology.

For osteomyelitis, said Dr. Viglianti, FDG-PET may have limited utility; it might be most useful when MRI is contraindicated. Within the study population, the investigators identified a patient who had chills and fever along with focal tenderness over the lumbar spine in the context of recent pyelonephritis of a graft kidney. Here, MRI findings were suspicious for osteomyelitis and diskitis, and the FDG uptake at the L4-L5 vertebral levels confirmed the MRI results.

When a patient with a prosthetic valve is suspected of having endocarditis, “cardiac PET/CT may be of high diagnostic value,” said Dr. Viglianti. For patients with endocarditis of native valves, though, a full-body FDG-PET/CT scan may spot septic emboli. A patient identified in the investigators’ review had been admitted for methicillin-resistant Staphylococcus aureus endocarditis. The patient, who had a history of intravenous drug use, received a transesophageal echocardiogram that found severe tricuspid valve regurgitation and vegetations. The whole-body PET/CT scan, though, revealed avid uptake in both buttocks, as well as thigh, ankle and calf muscles – a pattern “suspicious for infectious myositis,” said the researchers.

In discussion during the poster session, Dr. Viglianti said that, although reimbursement for PET/CT scans for infectious etiologies might not be feasible, it can still be a reasonable and even cost-effective choice. At his institution, he said, the requisite radioisotope is made in-house, twice daily, so it’s relatively easy to arrange scans. Since PET/CT scans can be acquired relatively quickly and there’s no delay while waiting for radiotracer uptake, clinical decisions can be made more quickly than when waiting for bone uptake for a technetium-99 scan, he said. This can have the effect of saving a night of hospitalization in many cases.

Dr. Viglianti and Ms. Menon reported that they had no relevant conflicts of interest. No outside sources of funding were reported.

koakes@mdedge.com

SOURCE: Menon A et al. RSNA 2019, Abstract NM203-SDSUB1.

CHICAGO – Dual positron emission tomography-computed tomography (PET/CT) scans changed the treatment course of nearly half of patients whose scans were positive for infection. In a single-center systematic review of 18fluorodeoxyglucose (FDG)–PET/CT scans, 55 of the 138 scans (40%) changed clinical management.

Kari Oakes/MDedge News

Presenting the findings at the annual meeting of the Radiological Society of North America, Benjamin Viglianti, MD, PhD, said that PET/CT had particular utility in cases of bacteremia and endocarditis, in which the scans changed treatment in 46% of those cases.

Dr. Viglianti, a radiologist at the University of Michigan, Ann Arbor, explained that medical student and first author Anitha Menon, himself, and their collaborators deliberately used a broad definition of clinical management change. The management course was considered to change not only if an unknown infection site was discovered or if a new intervention was initiated after the scan, but also if antibiotic choice or duration was changed or an additional specialty was consulted.

Scans were included in the study if an infectious etiology was found in the scan and if the patient received an infectious disease consult. Bacteremia and endocarditis were the most frequent indications for scans and also the indications for which management was most frequently changed. When a vascular cause was the indication for the scan, management changed 41% of the time. For fevers of unknown origin, the scan changed management in 30% of the cases, while for osteomyelitis, management was changed for 28% of patients.

The investigators identified several broad themes from their review that pointed toward when clinicians might consider FDG-PET/CT imaging in infectious disease management.

The first, said Dr. Viglianti, was that “for patients with suspected vascular graft infection, PET/CT using FDG may be a good first-choice imaging modality.” He pointed to an illustrative case of a patient who was 1 month out from open repair of a thoracoabdominal aortic aneurysm. The patient had abdominal pain, epigastric tenderness and nausea, as well as an erythematous incision site. A CT scan just revealed an abdominal fluid collection, but the PET/CT scan showed radiotracer uptake at the prior repair site, indicating infection.

For patients with bacteremia, the investigators judged that FDG-PET/CT might be particularly useful in patients who have a graft, prosthetic valve, or cardiac device. Here, Dr. Viglianti and his collaborators highlighted the scan of a woman with DiGeorge syndrome who had received aortic root replacement for truncus arteriosis. She had been found to have persistent enterococcal bacteremia at high levels, but had been symptom free. To take a close look at the suspected infectious nidus, a transesophageal echocardiogram had been obtained, but this study didn’t turn up any clear masses or vegetations. The PET/CT scan, though, revealed avid FDG uptake in the area of the prosthesis.

Management course was not likely to be changed for patients with fever of unknown origin, but the investigators did note that whole-body PET/CT was useful to distinguish infectious etiologies from hematologic and oncologic processes. Their review included a patient who had Crohn’s disease and fever, myalgias, and upper abdominal pain, as well as liver enzyme elevation. The PET/CT showed radiotracer uptake within the spleen, which was enlarged. The scan also showed bone marrow uptake; these findings pointed toward hemophagocytic lymphohistiocytosis rather than an infectious etiology.

For osteomyelitis, said Dr. Viglianti, FDG-PET may have limited utility; it might be most useful when MRI is contraindicated. Within the study population, the investigators identified a patient who had chills and fever along with focal tenderness over the lumbar spine in the context of recent pyelonephritis of a graft kidney. Here, MRI findings were suspicious for osteomyelitis and diskitis, and the FDG uptake at the L4-L5 vertebral levels confirmed the MRI results.

When a patient with a prosthetic valve is suspected of having endocarditis, “cardiac PET/CT may be of high diagnostic value,” said Dr. Viglianti. For patients with endocarditis of native valves, though, a full-body FDG-PET/CT scan may spot septic emboli. A patient identified in the investigators’ review had been admitted for methicillin-resistant Staphylococcus aureus endocarditis. The patient, who had a history of intravenous drug use, received a transesophageal echocardiogram that found severe tricuspid valve regurgitation and vegetations. The whole-body PET/CT scan, though, revealed avid uptake in both buttocks, as well as thigh, ankle and calf muscles – a pattern “suspicious for infectious myositis,” said the researchers.

In discussion during the poster session, Dr. Viglianti said that, although reimbursement for PET/CT scans for infectious etiologies might not be feasible, it can still be a reasonable and even cost-effective choice. At his institution, he said, the requisite radioisotope is made in-house, twice daily, so it’s relatively easy to arrange scans. Since PET/CT scans can be acquired relatively quickly and there’s no delay while waiting for radiotracer uptake, clinical decisions can be made more quickly than when waiting for bone uptake for a technetium-99 scan, he said. This can have the effect of saving a night of hospitalization in many cases.

Dr. Viglianti and Ms. Menon reported that they had no relevant conflicts of interest. No outside sources of funding were reported.

koakes@mdedge.com

SOURCE: Menon A et al. RSNA 2019, Abstract NM203-SDSUB1.

CHICAGO – Dual positron emission tomography-computed tomography (PET/CT) scans changed the treatment course of nearly half of patients whose scans were positive for infection. In a single-center systematic review of 18fluorodeoxyglucose (FDG)–PET/CT scans, 55 of the 138 scans (40%) changed clinical management.

Kari Oakes/MDedge News

Presenting the findings at the annual meeting of the Radiological Society of North America, Benjamin Viglianti, MD, PhD, said that PET/CT had particular utility in cases of bacteremia and endocarditis, in which the scans changed treatment in 46% of those cases.

Dr. Viglianti, a radiologist at the University of Michigan, Ann Arbor, explained that medical student and first author Anitha Menon, himself, and their collaborators deliberately used a broad definition of clinical management change. The management course was considered to change not only if an unknown infection site was discovered or if a new intervention was initiated after the scan, but also if antibiotic choice or duration was changed or an additional specialty was consulted.

Scans were included in the study if an infectious etiology was found in the scan and if the patient received an infectious disease consult. Bacteremia and endocarditis were the most frequent indications for scans and also the indications for which management was most frequently changed. When a vascular cause was the indication for the scan, management changed 41% of the time. For fevers of unknown origin, the scan changed management in 30% of the cases, while for osteomyelitis, management was changed for 28% of patients.

The investigators identified several broad themes from their review that pointed toward when clinicians might consider FDG-PET/CT imaging in infectious disease management.

The first, said Dr. Viglianti, was that “for patients with suspected vascular graft infection, PET/CT using FDG may be a good first-choice imaging modality.” He pointed to an illustrative case of a patient who was 1 month out from open repair of a thoracoabdominal aortic aneurysm. The patient had abdominal pain, epigastric tenderness and nausea, as well as an erythematous incision site. A CT scan just revealed an abdominal fluid collection, but the PET/CT scan showed radiotracer uptake at the prior repair site, indicating infection.

For patients with bacteremia, the investigators judged that FDG-PET/CT might be particularly useful in patients who have a graft, prosthetic valve, or cardiac device. Here, Dr. Viglianti and his collaborators highlighted the scan of a woman with DiGeorge syndrome who had received aortic root replacement for truncus arteriosis. She had been found to have persistent enterococcal bacteremia at high levels, but had been symptom free. To take a close look at the suspected infectious nidus, a transesophageal echocardiogram had been obtained, but this study didn’t turn up any clear masses or vegetations. The PET/CT scan, though, revealed avid FDG uptake in the area of the prosthesis.

Management course was not likely to be changed for patients with fever of unknown origin, but the investigators did note that whole-body PET/CT was useful to distinguish infectious etiologies from hematologic and oncologic processes. Their review included a patient who had Crohn’s disease and fever, myalgias, and upper abdominal pain, as well as liver enzyme elevation. The PET/CT showed radiotracer uptake within the spleen, which was enlarged. The scan also showed bone marrow uptake; these findings pointed toward hemophagocytic lymphohistiocytosis rather than an infectious etiology.

For osteomyelitis, said Dr. Viglianti, FDG-PET may have limited utility; it might be most useful when MRI is contraindicated. Within the study population, the investigators identified a patient who had chills and fever along with focal tenderness over the lumbar spine in the context of recent pyelonephritis of a graft kidney. Here, MRI findings were suspicious for osteomyelitis and diskitis, and the FDG uptake at the L4-L5 vertebral levels confirmed the MRI results.

When a patient with a prosthetic valve is suspected of having endocarditis, “cardiac PET/CT may be of high diagnostic value,” said Dr. Viglianti. For patients with endocarditis of native valves, though, a full-body FDG-PET/CT scan may spot septic emboli. A patient identified in the investigators’ review had been admitted for methicillin-resistant Staphylococcus aureus endocarditis. The patient, who had a history of intravenous drug use, received a transesophageal echocardiogram that found severe tricuspid valve regurgitation and vegetations. The whole-body PET/CT scan, though, revealed avid uptake in both buttocks, as well as thigh, ankle and calf muscles – a pattern “suspicious for infectious myositis,” said the researchers.

In discussion during the poster session, Dr. Viglianti said that, although reimbursement for PET/CT scans for infectious etiologies might not be feasible, it can still be a reasonable and even cost-effective choice. At his institution, he said, the requisite radioisotope is made in-house, twice daily, so it’s relatively easy to arrange scans. Since PET/CT scans can be acquired relatively quickly and there’s no delay while waiting for radiotracer uptake, clinical decisions can be made more quickly than when waiting for bone uptake for a technetium-99 scan, he said. This can have the effect of saving a night of hospitalization in many cases.

Dr. Viglianti and Ms. Menon reported that they had no relevant conflicts of interest. No outside sources of funding were reported.

koakes@mdedge.com

SOURCE: Menon A et al. RSNA 2019, Abstract NM203-SDSUB1.