Approximately 1 in 4 people ages 18 years and older and 1 in 3 people ages 18 to 25 years had a mental illness in the past year, according to the 2021 National Survey of Drug Use and Health.¹ The survey also found that adults ages 18 to 25 years had the highest rate of serious mental illness but the lowest treatment rate compared to other adult age groups.¹ Unfortunately, more than 60% of patients receiving mental health treatment fail to benefit to a clinically meaningful degree.²

However, there is growing evidence that referring patients to behavioral health practitioners (BHPs) with outcome-measured skills that meet the patient’s specific needs can have a dramatic and positive impact. There are 2 main steps to pairing patients with an appropriate BHP: (1) use of measurement-based care data that can be analyzed at the patient and therapist level, and (2) data-driven referrals that pair patients with BHPs based on such routine outcome monitoring data (paired-on outcome data).

Psychotherapy’s slow road toward measurement-based care

Routine outcome monitoring is the systematic measurement of symptoms and functioning during treatment. It serves multiple functions, including program evaluation and benchmarking of patient improvement rates. Moreover, routine outcome monitoring–­derived feedback (based on repeated patient outcome measurements) can inform personalized and responsive care decisions throughout treatment.

For all intents and purposes, routine outcome monitoring plus feedback is synonymous with measurement-based care, which is becoming the preferred term in psychotherapy.³ Although measurement-based care is often the standard of practice for treating physical health conditions, the adoption of measurement-based care practices for treating mental health conditions remains low.³ The implementation of routine outcome monitoring is the lynchpin of measurement-based care, which in psychotherapy includes³:

• routinely administered symptom/functioning measure, ideally before each clinical encounter,
• practitioner review of these patient-level data,
• patient review of these data with their practitioner, and
• collaborative reevaluation of the person-specific treatment plan informed by these data.

CASE SCENARIO

Violeta W is a 33-year-old woman who presented to her family physician for her annual wellness exam. Prior to the exam, the medical assistant administered a Patient Health ­Questionnaire-9 (PHQ-9) to screen for depressive symptoms. Ms. W’s score was 20 out of 27, suggestive of depression. To further assess the severity of depressive symptoms and their effect on daily function, the physician reviewed responses to the questionnaire with her and discussed treatment options. Ms. W was most interested in trying a low-dose selective serotonin reuptake inhibitor (SSRI).

At her follow-up visit 4 weeks later, the medical assistant re-administered the PHQ-9. The physician then reviewed Ms. W’s responses­ with her and, based on Ms. W’s subjective report and objective symptoms (still a score of 20 out of 27 on the PHQ-9), increased her SSRI dose. At each subsequent visit, Ms. W completed a PHQ-9 and reviewed responses and depressive symptoms with her physician.

The value of measurement-based care in mental health care

A narrative review by Lewis et al³ of 21 randomized controlled clinical trials (RCTs) across a range of age groups (eg, adolescents, young adults, adults), disorders (eg, anxiety, mood), and settings (eg, outpatient, inpatient) found that in at least 9 review articles, measurement-based care was associated with significantly improved outcomes vs usual care (ie, treatment without routine outcome monitoring plus feedback). The average increase in treatment effect size was about 30% when treatment was accompanied by measurement-based care.³

Continue to: Moreover, a recent within-patient meta-analysis...

Routine outcome monitoring– derived feedback can inform personalized and responsive care decisions throughout treatment.

Moreover, a recent within-patient meta-analysis by de Jong et al⁴ shows that ­measurement-based care yields a small but significant increase in therapeutic outcomes (d = .15). Use of measurement-based care also is associated with improved communication between the patient and therapist.⁵ In pharmacotherapy practice, measurement-based care has been shown to predict rapid dose increases and changes in medication, when necessary; faster recovery rates; higher response rates to treatment³; and fewer ­dropouts.⁴

Perhaps one of the best-studied benefits of measurement-based mental health care is the ability to predict deterioration in care (ie, patients who are off-track in a way that practitioners often miss without the help of routine outcome monitoring data).^6,7 Studies show that without a data-informed approach to care, some forms of psychotherapy or therapy with BHPs who are not sufficiently skilled in treating a given diagnosis increase symptoms or create significant harmful and iatrogenic effects.^8-10 Conversely, the meta-analysis by de Jong et al⁴ found a lower percentage of deterioration in patients receiving ­measurement-based care. The difference in deterioration was significant: An average of 5.4% of patients in control conditions deteriorated compared to an average of 4.6% in feedback (measurement-based care) groups. There were even larger effect sizes when therapists received training in the feedback system.⁴

Routine outcome monitoring without a dialogue between patient and practitioner about the assessments (eg, ignoring complete measurement-based care requirements) may be inadequate. A recent review by Muir et al⁶ found no differences in patient outcomes when data were used solely for aggregate quality improvement activities, suggesting the need for practitioners to review results of routine outcome monitoring assessments with patients and use data to alter care when necessary.

Measurement-based care is believed to deliver benefits and reduce harm by enhancing and encouraging active patient involvement, improving patient understanding of symptoms, promoting better communication, and facilitating better care coordination.³ The benefits of measurement-based care can be enhanced with a comprehensive core routine outcome monitoring tool and the level of monitoring-generated information delivered for multiple stakeholders (eg, patient, therapist, clinic).¹¹

A look at multidimensional assessment

The features of routine outcome monitoring tools vary significantly.¹² Some measures assess single-symptom or problem domains (eg, PHQ-9 for depression or Generalized Anxiety Disorder-7 [GAD-7] scale for anxiety) or multiple dimensions (multidimensional routine outcome monitoring).Multidimensional routine outcome monitoring may have benefits over single-domain measures. Single­-domain measures and the subscales or factors of more comprehensive multidimensional routine outcome monitoring assessments should possess adequate specificity and sensitivity.

Continue to: Some recent research findings...

Some recent research findings question the construct validity of brief single-domain measures of common presenting problems, such as depression and anxiety. For example, results from a factor analysis of the PHQ-9 and GAD-7 scale in patients with traumatic brain injury suggest these tools measure 1 psychological construct that includes depression and the cognitive components of anxiety (eg, worry)¹³—a finding consistent with those of other tools.¹⁴ Similarly, a larger study of 7763 BH patients found that a single factor accounted for most of the variance of the 2 combined measures, with no set of factors meeting the exacting standards used to develop multidimensional routine outcome monitoring.¹⁵ These findings suggest that the PHQ-9 and GAD-7 largely overlap and are not measuring different aspects of health as most practitioners believe (eg, depression and anxiety).

In commonly used assessments, ­multiple-factor analytic studies with high standards have supported the construct validity of domain-specific subscales, indicating that the various questions tap into different constructs of psychological health.^14,16,17

Perhaps one of the best-studied benefits of mental health measurementbased care is the ability to predict deterioration in care.

Beyond multiple domain–specific indicators, multidimensional routine outcome measurements provide a global total score that minimizes Type I (false-positive conclusion) and Type II (false-negative conclusion) errors in tracking patient improvement or deterioration.¹⁸ As one would expect, multidimensional routine outcome monitoring generally includes more items than single-domain measures; however, this comes with a trade-off. If there are specificity and sensitivity concerns with an ultra-brief single-domain measure, an alternative to a core multidimensional routine outcome measurement is to aggregate a series of single-domain measures into a battery of patient self-reports. However, this approach may take longer for patients to complete since they would have to shift among the varying response sets and wording across the unique single-domain measures.

In addition, the standardization/­normalization of multidimensional routine outcome monitoring likely makes interpretation easier than referring to norms and clinical severity cutoffs for many distinct measures. Furthermore, increased specificity enhances predictive power and allows BHPs to screen and track other conditions besides depression and anxiety. (It is worth noting that there are no known studies that have looked at the difference in time to administer or ease of interpretation of multidimensional routine outcome monitoring tools vs multiple single-domain measures.)

Two multidimensional routine outcome monitoring tools that cover a comprehensive series of discrete symptom and functional domains are the Treatment Outcome Package¹² and Counseling Center ­Assessment of Psychological Symptoms.¹⁶ These tools, which include subscales beyond general depression and anxiety (eg, sleep, substance misuse, social conflict), take 7 to 10 minutes to complete and provide outcome results across 12 symptom and 8 functional dimensions. As an example, the Treatment Outcome Package has good psychometric qualities (eg, reliability, construct and concurrent validity) for adults,¹² children,^14,19 and adolescents,¹⁹ and can be administered through a secure online data collection portal. The Counseling Center Assessment of Psychological Symptoms has demonstrated high construct validity and good convergent validity.¹⁶ These assessments can be administered in paper or digital (eg, electronic medical record portal, smartphone) format.²⁰

Continue to: CASE SCENARIO

CASE SCENARIO

Ms. W’s physician asked her to go online using her phone and answer the questions in the Treatment Outcome Package. Her results, which she viewed with her physician, were displayed in graph form (FIGURE). Her scores were represented in Z scores normalized to the general population, with “0” representing the general, nontreatment-seeking population average and positive scores representing the number of standard deviations (SDs) more severe than the general population average.

Although this assessment scored Ms. W’s clinically elevated depression as mild, it revealed abnormalities in 3 other domains. Sexual functioning issues represented the most abnormal domain at greater than 3 SDs (more severe than the general population), followed by poor life quality and school/work functioning.

After reviewing Ms. W’s report, her physician decided that pharmacologic management alone (for depression) was not the most appropriate treatment course. Therefore, her physician recommended psychotherapy in addition to the SSRI she was taking. Ms. W agreed to a customized referral for psychotherapy.

Data-driven referrals

When psychotherapy is chosen as a treatment, the individual BHP is an active component of that treatment. Consequently, it is essential to customize referrals to match a patient’s most elevated mental health concerns with a therapist who will most effectively treat those domains. It is rare for a BHP to be skilled in treating every mental health domain.⁹ Multiple studies have shown that BHPs have identifiable treatment skills in specific domains, which physicians should consider when making referrals.^9,21,22 These studies demonstrate the utility of aggregating patient-level routine outcome monitoring data to better understand therapist-level (and ultimately clinic- and system-level) outcomes.

It is essential to customize referrals to match a patient’s most elevated mental health concerns with a therapist who will most effectively treat those domains.

Additionally, recent research has tested this idea prospectively. An RCT funded by the Patient-Centered Outcome Research Institute and published in JAMA Psychiatry showed a significant and positive effect on patient outcomes (ie, reductions in general impairment, impairment involving a patient’s most elevated domain, and global distress) using paired-on outcome data matching vs as-usual matching protocols (eg, therapist self-defined areas of specialty).²² In the RCT, the most effective matching protocol was a combination of eliminating harm and matching the patient on their 3 most problematic domains (the highest match level). These patients ended care as healthy as the general population after 16 weeks of treatment. A random 1-year follow-up assessment from the original RCT showed that most patients who had been matched had maintained their improvement.²³

Continue to: Therefore, a multidimensional routine outcome...

Therefore, a multidimensional routine outcome monitoring tool can be used to identify a BHP’s relative strengths and weaknesses across multiple outcome domains. Within a system of care, a sample of BHPs will possess varying outcome-domain profiles. When a new patient is seeking a referral to a BHP, these profiles (or domain-specific outcome track records) can be used to support paired-on outcome data matching. Specifically, a new patient completes the multidimensional routine outcome monitoring tool at pretreatment, and the results reveal the outcome domains on which the patient is most clinically severe. This pattern of domain-specific severity then can be used to pair the new patient with a BHP who has demonstrated success in addressing the same outcome domain(s). This approach matches a new patient to a BHP with established expertise based on routine outcome monitoring.

Retrospective and prospective studies have found that most BHPs have stable performance in their strengths and weaknesses.^11,21 One study found that assessing BHP performance with their most recent 30 patients can reliably predict future performance with their next 30 patients.²⁴ This predictability in a practitioner’s outcomes suggests report cards that are updated frequently can be utilized to make case assignments within BH or referrals to a specific BHP from primary care.

Making a paired-on outcome data–matched referral

Making customized BH referrals requires access to information about a practitioner’s previous routine outcome monitoring data per clinical domain (eg, suicidality, violence, quality of life) from their most recent patients. Previous research suggests that follow-up data from a minimum of 15 patients is necessary to make a reliable evaluation of a practitioner’s strengths and weaknesses (ie, effectiveness “report card”) per clinical ­domain.²⁴

Previous research suggests that follow-up data from a minimum of 15 patients is necessary to make a reliable evaluation of a practitioner’s strengths and weaknesses.

Few, if any, physicians have access to this level of updated outcome data from their referral network. To facilitate widespread use of paired-on outcome data matching, a new Web system (MatchedTherapists.com) will allow the general public and PCPs to access these grades. As a public service option, this site currently allows for a self-assessment using the Treatment Outcome Package. Pending versions will generate paired-on outcome data grades, and users will receive a list of local therapists available for in-person appointments as well as therapists available for virtual appointments. The paired-on outcome data grades are delivered in school-based letter grades. An “A+,” for example, represents the best matching grade. Users also will be able to sort and filter results for other criteria such as telemedicine, insurance, age, gender, and appointment availability. Currently, there are more than 77,000 therapists listed on the site nationwide. A basic listing is free.

CASE SCENARIO

After Ms. W took the multidimensional routine outcome assessment online, she received a list of therapists rank-ordered by paired-on outcome data grade, with the “A+” matches listed first. Three of the best-matched referrals accepted her insurance and were willing to see her through telemedicine. Therapists with available in-person appointments had a “B” grade. After discussing the options with her physician, Ms. W opted for telehealth counseling with the therapist whose profile she liked best. The therapist and PCP tracked her progress through routine outcome monitoring reporting until all her symptoms became subclinical.

Continue to: The future of a "referral bridge"

In this article, we present a solution to a common issue faced by mental health care patients: failure to benefit meaningfully from mental health treatment. Matching patients to specific BHPs based on effectiveness data regarding the therapist’s strengths and skills can improve patient outcomes and reduce harm. In addition, patients appear to value this approach. A Robert Wood Johnson Foundation–­funded study demonstrated that patients value seeing practitioners who have a track record of successfully treating previous patients with similar issues.^25,26 In many cases, patients indicated they would prioritize this matching process over other factors such as practitioners with a higher number of years of experience or the same demographic characteristics as the patient.^25,26

In many cases, patients indicated they would prioritize this matching process over other factors such as practitioners with a higher number of years of experience.

These findings may represent a new area in the science of health care. Over the past century, major advances in diagnosis and treatment—the 2 primary pillars of health care—have turned the art of medicine into a science. However, the art of making referrals has not advanced commensurately, as there has been little attention focused on the “referral bridge” between these 2 pillars. As the studies reviewed in this paper demonstrate, a referral bridge deserves exploration in all fields of medicine.

CORRESPONDENCE
David R. Kraus, PhD, 1 Speen Street, Framingham, MA 01701; [email protected]

Approximately 1 in 4 people ages 18 years and older and 1 in 3 people ages 18 to 25 years had a mental illness in the past year, according to the 2021 National Survey of Drug Use and Health.¹ The survey also found that adults ages 18 to 25 years had the highest rate of serious mental illness but the lowest treatment rate compared to other adult age groups.¹ Unfortunately, more than 60% of patients receiving mental health treatment fail to benefit to a clinically meaningful degree.²

However, there is growing evidence that referring patients to behavioral health practitioners (BHPs) with outcome-measured skills that meet the patient’s specific needs can have a dramatic and positive impact. There are 2 main steps to pairing patients with an appropriate BHP: (1) use of measurement-based care data that can be analyzed at the patient and therapist level, and (2) data-driven referrals that pair patients with BHPs based on such routine outcome monitoring data (paired-on outcome data).

Psychotherapy’s slow road toward measurement-based care

Routine outcome monitoring is the systematic measurement of symptoms and functioning during treatment. It serves multiple functions, including program evaluation and benchmarking of patient improvement rates. Moreover, routine outcome monitoring–­derived feedback (based on repeated patient outcome measurements) can inform personalized and responsive care decisions throughout treatment.

For all intents and purposes, routine outcome monitoring plus feedback is synonymous with measurement-based care, which is becoming the preferred term in psychotherapy.³ Although measurement-based care is often the standard of practice for treating physical health conditions, the adoption of measurement-based care practices for treating mental health conditions remains low.³ The implementation of routine outcome monitoring is the lynchpin of measurement-based care, which in psychotherapy includes³:

• routinely administered symptom/functioning measure, ideally before each clinical encounter,
• practitioner review of these patient-level data,
• patient review of these data with their practitioner, and
• collaborative reevaluation of the person-specific treatment plan informed by these data.

CASE SCENARIO

Violeta W is a 33-year-old woman who presented to her family physician for her annual wellness exam. Prior to the exam, the medical assistant administered a Patient Health ­Questionnaire-9 (PHQ-9) to screen for depressive symptoms. Ms. W’s score was 20 out of 27, suggestive of depression. To further assess the severity of depressive symptoms and their effect on daily function, the physician reviewed responses to the questionnaire with her and discussed treatment options. Ms. W was most interested in trying a low-dose selective serotonin reuptake inhibitor (SSRI).

At her follow-up visit 4 weeks later, the medical assistant re-administered the PHQ-9. The physician then reviewed Ms. W’s responses­ with her and, based on Ms. W’s subjective report and objective symptoms (still a score of 20 out of 27 on the PHQ-9), increased her SSRI dose. At each subsequent visit, Ms. W completed a PHQ-9 and reviewed responses and depressive symptoms with her physician.

The value of measurement-based care in mental health care

A narrative review by Lewis et al³ of 21 randomized controlled clinical trials (RCTs) across a range of age groups (eg, adolescents, young adults, adults), disorders (eg, anxiety, mood), and settings (eg, outpatient, inpatient) found that in at least 9 review articles, measurement-based care was associated with significantly improved outcomes vs usual care (ie, treatment without routine outcome monitoring plus feedback). The average increase in treatment effect size was about 30% when treatment was accompanied by measurement-based care.³

Continue to: Moreover, a recent within-patient meta-analysis...

Routine outcome monitoring– derived feedback can inform personalized and responsive care decisions throughout treatment.

Moreover, a recent within-patient meta-analysis by de Jong et al⁴ shows that ­measurement-based care yields a small but significant increase in therapeutic outcomes (d = .15). Use of measurement-based care also is associated with improved communication between the patient and therapist.⁵ In pharmacotherapy practice, measurement-based care has been shown to predict rapid dose increases and changes in medication, when necessary; faster recovery rates; higher response rates to treatment³; and fewer ­dropouts.⁴

Perhaps one of the best-studied benefits of measurement-based mental health care is the ability to predict deterioration in care (ie, patients who are off-track in a way that practitioners often miss without the help of routine outcome monitoring data).^6,7 Studies show that without a data-informed approach to care, some forms of psychotherapy or therapy with BHPs who are not sufficiently skilled in treating a given diagnosis increase symptoms or create significant harmful and iatrogenic effects.^8-10 Conversely, the meta-analysis by de Jong et al⁴ found a lower percentage of deterioration in patients receiving ­measurement-based care. The difference in deterioration was significant: An average of 5.4% of patients in control conditions deteriorated compared to an average of 4.6% in feedback (measurement-based care) groups. There were even larger effect sizes when therapists received training in the feedback system.⁴

Routine outcome monitoring without a dialogue between patient and practitioner about the assessments (eg, ignoring complete measurement-based care requirements) may be inadequate. A recent review by Muir et al⁶ found no differences in patient outcomes when data were used solely for aggregate quality improvement activities, suggesting the need for practitioners to review results of routine outcome monitoring assessments with patients and use data to alter care when necessary.

Measurement-based care is believed to deliver benefits and reduce harm by enhancing and encouraging active patient involvement, improving patient understanding of symptoms, promoting better communication, and facilitating better care coordination.³ The benefits of measurement-based care can be enhanced with a comprehensive core routine outcome monitoring tool and the level of monitoring-generated information delivered for multiple stakeholders (eg, patient, therapist, clinic).¹¹

A look at multidimensional assessment

The features of routine outcome monitoring tools vary significantly.¹² Some measures assess single-symptom or problem domains (eg, PHQ-9 for depression or Generalized Anxiety Disorder-7 [GAD-7] scale for anxiety) or multiple dimensions (multidimensional routine outcome monitoring).Multidimensional routine outcome monitoring may have benefits over single-domain measures. Single­-domain measures and the subscales or factors of more comprehensive multidimensional routine outcome monitoring assessments should possess adequate specificity and sensitivity.

Continue to: Some recent research findings...

Some recent research findings question the construct validity of brief single-domain measures of common presenting problems, such as depression and anxiety. For example, results from a factor analysis of the PHQ-9 and GAD-7 scale in patients with traumatic brain injury suggest these tools measure 1 psychological construct that includes depression and the cognitive components of anxiety (eg, worry)¹³—a finding consistent with those of other tools.¹⁴ Similarly, a larger study of 7763 BH patients found that a single factor accounted for most of the variance of the 2 combined measures, with no set of factors meeting the exacting standards used to develop multidimensional routine outcome monitoring.¹⁵ These findings suggest that the PHQ-9 and GAD-7 largely overlap and are not measuring different aspects of health as most practitioners believe (eg, depression and anxiety).

In commonly used assessments, ­multiple-factor analytic studies with high standards have supported the construct validity of domain-specific subscales, indicating that the various questions tap into different constructs of psychological health.^14,16,17

Perhaps one of the best-studied benefits of mental health measurementbased care is the ability to predict deterioration in care.

Beyond multiple domain–specific indicators, multidimensional routine outcome measurements provide a global total score that minimizes Type I (false-positive conclusion) and Type II (false-negative conclusion) errors in tracking patient improvement or deterioration.¹⁸ As one would expect, multidimensional routine outcome monitoring generally includes more items than single-domain measures; however, this comes with a trade-off. If there are specificity and sensitivity concerns with an ultra-brief single-domain measure, an alternative to a core multidimensional routine outcome measurement is to aggregate a series of single-domain measures into a battery of patient self-reports. However, this approach may take longer for patients to complete since they would have to shift among the varying response sets and wording across the unique single-domain measures.

In addition, the standardization/­normalization of multidimensional routine outcome monitoring likely makes interpretation easier than referring to norms and clinical severity cutoffs for many distinct measures. Furthermore, increased specificity enhances predictive power and allows BHPs to screen and track other conditions besides depression and anxiety. (It is worth noting that there are no known studies that have looked at the difference in time to administer or ease of interpretation of multidimensional routine outcome monitoring tools vs multiple single-domain measures.)

Two multidimensional routine outcome monitoring tools that cover a comprehensive series of discrete symptom and functional domains are the Treatment Outcome Package¹² and Counseling Center ­Assessment of Psychological Symptoms.¹⁶ These tools, which include subscales beyond general depression and anxiety (eg, sleep, substance misuse, social conflict), take 7 to 10 minutes to complete and provide outcome results across 12 symptom and 8 functional dimensions. As an example, the Treatment Outcome Package has good psychometric qualities (eg, reliability, construct and concurrent validity) for adults,¹² children,^14,19 and adolescents,¹⁹ and can be administered through a secure online data collection portal. The Counseling Center Assessment of Psychological Symptoms has demonstrated high construct validity and good convergent validity.¹⁶ These assessments can be administered in paper or digital (eg, electronic medical record portal, smartphone) format.²⁰

Continue to: CASE SCENARIO

CASE SCENARIO

Ms. W’s physician asked her to go online using her phone and answer the questions in the Treatment Outcome Package. Her results, which she viewed with her physician, were displayed in graph form (FIGURE). Her scores were represented in Z scores normalized to the general population, with “0” representing the general, nontreatment-seeking population average and positive scores representing the number of standard deviations (SDs) more severe than the general population average.

Although this assessment scored Ms. W’s clinically elevated depression as mild, it revealed abnormalities in 3 other domains. Sexual functioning issues represented the most abnormal domain at greater than 3 SDs (more severe than the general population), followed by poor life quality and school/work functioning.

After reviewing Ms. W’s report, her physician decided that pharmacologic management alone (for depression) was not the most appropriate treatment course. Therefore, her physician recommended psychotherapy in addition to the SSRI she was taking. Ms. W agreed to a customized referral for psychotherapy.

Data-driven referrals

When psychotherapy is chosen as a treatment, the individual BHP is an active component of that treatment. Consequently, it is essential to customize referrals to match a patient’s most elevated mental health concerns with a therapist who will most effectively treat those domains. It is rare for a BHP to be skilled in treating every mental health domain.⁹ Multiple studies have shown that BHPs have identifiable treatment skills in specific domains, which physicians should consider when making referrals.^9,21,22 These studies demonstrate the utility of aggregating patient-level routine outcome monitoring data to better understand therapist-level (and ultimately clinic- and system-level) outcomes.

It is essential to customize referrals to match a patient’s most elevated mental health concerns with a therapist who will most effectively treat those domains.

Additionally, recent research has tested this idea prospectively. An RCT funded by the Patient-Centered Outcome Research Institute and published in JAMA Psychiatry showed a significant and positive effect on patient outcomes (ie, reductions in general impairment, impairment involving a patient’s most elevated domain, and global distress) using paired-on outcome data matching vs as-usual matching protocols (eg, therapist self-defined areas of specialty).²² In the RCT, the most effective matching protocol was a combination of eliminating harm and matching the patient on their 3 most problematic domains (the highest match level). These patients ended care as healthy as the general population after 16 weeks of treatment. A random 1-year follow-up assessment from the original RCT showed that most patients who had been matched had maintained their improvement.²³

Continue to: Therefore, a multidimensional routine outcome...

Therefore, a multidimensional routine outcome monitoring tool can be used to identify a BHP’s relative strengths and weaknesses across multiple outcome domains. Within a system of care, a sample of BHPs will possess varying outcome-domain profiles. When a new patient is seeking a referral to a BHP, these profiles (or domain-specific outcome track records) can be used to support paired-on outcome data matching. Specifically, a new patient completes the multidimensional routine outcome monitoring tool at pretreatment, and the results reveal the outcome domains on which the patient is most clinically severe. This pattern of domain-specific severity then can be used to pair the new patient with a BHP who has demonstrated success in addressing the same outcome domain(s). This approach matches a new patient to a BHP with established expertise based on routine outcome monitoring.

Retrospective and prospective studies have found that most BHPs have stable performance in their strengths and weaknesses.^11,21 One study found that assessing BHP performance with their most recent 30 patients can reliably predict future performance with their next 30 patients.²⁴ This predictability in a practitioner’s outcomes suggests report cards that are updated frequently can be utilized to make case assignments within BH or referrals to a specific BHP from primary care.

Making a paired-on outcome data–matched referral

Making customized BH referrals requires access to information about a practitioner’s previous routine outcome monitoring data per clinical domain (eg, suicidality, violence, quality of life) from their most recent patients. Previous research suggests that follow-up data from a minimum of 15 patients is necessary to make a reliable evaluation of a practitioner’s strengths and weaknesses (ie, effectiveness “report card”) per clinical ­domain.²⁴

Previous research suggests that follow-up data from a minimum of 15 patients is necessary to make a reliable evaluation of a practitioner’s strengths and weaknesses.

Few, if any, physicians have access to this level of updated outcome data from their referral network. To facilitate widespread use of paired-on outcome data matching, a new Web system (MatchedTherapists.com) will allow the general public and PCPs to access these grades. As a public service option, this site currently allows for a self-assessment using the Treatment Outcome Package. Pending versions will generate paired-on outcome data grades, and users will receive a list of local therapists available for in-person appointments as well as therapists available for virtual appointments. The paired-on outcome data grades are delivered in school-based letter grades. An “A+,” for example, represents the best matching grade. Users also will be able to sort and filter results for other criteria such as telemedicine, insurance, age, gender, and appointment availability. Currently, there are more than 77,000 therapists listed on the site nationwide. A basic listing is free.

CASE SCENARIO

After Ms. W took the multidimensional routine outcome assessment online, she received a list of therapists rank-ordered by paired-on outcome data grade, with the “A+” matches listed first. Three of the best-matched referrals accepted her insurance and were willing to see her through telemedicine. Therapists with available in-person appointments had a “B” grade. After discussing the options with her physician, Ms. W opted for telehealth counseling with the therapist whose profile she liked best. The therapist and PCP tracked her progress through routine outcome monitoring reporting until all her symptoms became subclinical.

Continue to: The future of a "referral bridge"

In this article, we present a solution to a common issue faced by mental health care patients: failure to benefit meaningfully from mental health treatment. Matching patients to specific BHPs based on effectiveness data regarding the therapist’s strengths and skills can improve patient outcomes and reduce harm. In addition, patients appear to value this approach. A Robert Wood Johnson Foundation–­funded study demonstrated that patients value seeing practitioners who have a track record of successfully treating previous patients with similar issues.^25,26 In many cases, patients indicated they would prioritize this matching process over other factors such as practitioners with a higher number of years of experience or the same demographic characteristics as the patient.^25,26

In many cases, patients indicated they would prioritize this matching process over other factors such as practitioners with a higher number of years of experience.

These findings may represent a new area in the science of health care. Over the past century, major advances in diagnosis and treatment—the 2 primary pillars of health care—have turned the art of medicine into a science. However, the art of making referrals has not advanced commensurately, as there has been little attention focused on the “referral bridge” between these 2 pillars. As the studies reviewed in this paper demonstrate, a referral bridge deserves exploration in all fields of medicine.

CORRESPONDENCE
David R. Kraus, PhD, 1 Speen Street, Framingham, MA 01701; [email protected]

Approximately 1 in 4 people ages 18 years and older and 1 in 3 people ages 18 to 25 years had a mental illness in the past year, according to the 2021 National Survey of Drug Use and Health.¹ The survey also found that adults ages 18 to 25 years had the highest rate of serious mental illness but the lowest treatment rate compared to other adult age groups.¹ Unfortunately, more than 60% of patients receiving mental health treatment fail to benefit to a clinically meaningful degree.²

However, there is growing evidence that referring patients to behavioral health practitioners (BHPs) with outcome-measured skills that meet the patient’s specific needs can have a dramatic and positive impact. There are 2 main steps to pairing patients with an appropriate BHP: (1) use of measurement-based care data that can be analyzed at the patient and therapist level, and (2) data-driven referrals that pair patients with BHPs based on such routine outcome monitoring data (paired-on outcome data).

Psychotherapy’s slow road toward measurement-based care

Routine outcome monitoring is the systematic measurement of symptoms and functioning during treatment. It serves multiple functions, including program evaluation and benchmarking of patient improvement rates. Moreover, routine outcome monitoring–­derived feedback (based on repeated patient outcome measurements) can inform personalized and responsive care decisions throughout treatment.

For all intents and purposes, routine outcome monitoring plus feedback is synonymous with measurement-based care, which is becoming the preferred term in psychotherapy.³ Although measurement-based care is often the standard of practice for treating physical health conditions, the adoption of measurement-based care practices for treating mental health conditions remains low.³ The implementation of routine outcome monitoring is the lynchpin of measurement-based care, which in psychotherapy includes³:

• routinely administered symptom/functioning measure, ideally before each clinical encounter,
• practitioner review of these patient-level data,
• patient review of these data with their practitioner, and
• collaborative reevaluation of the person-specific treatment plan informed by these data.

CASE SCENARIO

Violeta W is a 33-year-old woman who presented to her family physician for her annual wellness exam. Prior to the exam, the medical assistant administered a Patient Health ­Questionnaire-9 (PHQ-9) to screen for depressive symptoms. Ms. W’s score was 20 out of 27, suggestive of depression. To further assess the severity of depressive symptoms and their effect on daily function, the physician reviewed responses to the questionnaire with her and discussed treatment options. Ms. W was most interested in trying a low-dose selective serotonin reuptake inhibitor (SSRI).

At her follow-up visit 4 weeks later, the medical assistant re-administered the PHQ-9. The physician then reviewed Ms. W’s responses­ with her and, based on Ms. W’s subjective report and objective symptoms (still a score of 20 out of 27 on the PHQ-9), increased her SSRI dose. At each subsequent visit, Ms. W completed a PHQ-9 and reviewed responses and depressive symptoms with her physician.

The value of measurement-based care in mental health care

A narrative review by Lewis et al³ of 21 randomized controlled clinical trials (RCTs) across a range of age groups (eg, adolescents, young adults, adults), disorders (eg, anxiety, mood), and settings (eg, outpatient, inpatient) found that in at least 9 review articles, measurement-based care was associated with significantly improved outcomes vs usual care (ie, treatment without routine outcome monitoring plus feedback). The average increase in treatment effect size was about 30% when treatment was accompanied by measurement-based care.³

Continue to: Moreover, a recent within-patient meta-analysis...

Routine outcome monitoring– derived feedback can inform personalized and responsive care decisions throughout treatment.

Moreover, a recent within-patient meta-analysis by de Jong et al⁴ shows that ­measurement-based care yields a small but significant increase in therapeutic outcomes (d = .15). Use of measurement-based care also is associated with improved communication between the patient and therapist.⁵ In pharmacotherapy practice, measurement-based care has been shown to predict rapid dose increases and changes in medication, when necessary; faster recovery rates; higher response rates to treatment³; and fewer ­dropouts.⁴

Perhaps one of the best-studied benefits of measurement-based mental health care is the ability to predict deterioration in care (ie, patients who are off-track in a way that practitioners often miss without the help of routine outcome monitoring data).^6,7 Studies show that without a data-informed approach to care, some forms of psychotherapy or therapy with BHPs who are not sufficiently skilled in treating a given diagnosis increase symptoms or create significant harmful and iatrogenic effects.^8-10 Conversely, the meta-analysis by de Jong et al⁴ found a lower percentage of deterioration in patients receiving ­measurement-based care. The difference in deterioration was significant: An average of 5.4% of patients in control conditions deteriorated compared to an average of 4.6% in feedback (measurement-based care) groups. There were even larger effect sizes when therapists received training in the feedback system.⁴

Routine outcome monitoring without a dialogue between patient and practitioner about the assessments (eg, ignoring complete measurement-based care requirements) may be inadequate. A recent review by Muir et al⁶ found no differences in patient outcomes when data were used solely for aggregate quality improvement activities, suggesting the need for practitioners to review results of routine outcome monitoring assessments with patients and use data to alter care when necessary.

Measurement-based care is believed to deliver benefits and reduce harm by enhancing and encouraging active patient involvement, improving patient understanding of symptoms, promoting better communication, and facilitating better care coordination.³ The benefits of measurement-based care can be enhanced with a comprehensive core routine outcome monitoring tool and the level of monitoring-generated information delivered for multiple stakeholders (eg, patient, therapist, clinic).¹¹

A look at multidimensional assessment

The features of routine outcome monitoring tools vary significantly.¹² Some measures assess single-symptom or problem domains (eg, PHQ-9 for depression or Generalized Anxiety Disorder-7 [GAD-7] scale for anxiety) or multiple dimensions (multidimensional routine outcome monitoring).Multidimensional routine outcome monitoring may have benefits over single-domain measures. Single­-domain measures and the subscales or factors of more comprehensive multidimensional routine outcome monitoring assessments should possess adequate specificity and sensitivity.

Continue to: Some recent research findings...

Some recent research findings question the construct validity of brief single-domain measures of common presenting problems, such as depression and anxiety. For example, results from a factor analysis of the PHQ-9 and GAD-7 scale in patients with traumatic brain injury suggest these tools measure 1 psychological construct that includes depression and the cognitive components of anxiety (eg, worry)¹³—a finding consistent with those of other tools.¹⁴ Similarly, a larger study of 7763 BH patients found that a single factor accounted for most of the variance of the 2 combined measures, with no set of factors meeting the exacting standards used to develop multidimensional routine outcome monitoring.¹⁵ These findings suggest that the PHQ-9 and GAD-7 largely overlap and are not measuring different aspects of health as most practitioners believe (eg, depression and anxiety).

In commonly used assessments, ­multiple-factor analytic studies with high standards have supported the construct validity of domain-specific subscales, indicating that the various questions tap into different constructs of psychological health.^14,16,17

Perhaps one of the best-studied benefits of mental health measurementbased care is the ability to predict deterioration in care.

Beyond multiple domain–specific indicators, multidimensional routine outcome measurements provide a global total score that minimizes Type I (false-positive conclusion) and Type II (false-negative conclusion) errors in tracking patient improvement or deterioration.¹⁸ As one would expect, multidimensional routine outcome monitoring generally includes more items than single-domain measures; however, this comes with a trade-off. If there are specificity and sensitivity concerns with an ultra-brief single-domain measure, an alternative to a core multidimensional routine outcome measurement is to aggregate a series of single-domain measures into a battery of patient self-reports. However, this approach may take longer for patients to complete since they would have to shift among the varying response sets and wording across the unique single-domain measures.

In addition, the standardization/­normalization of multidimensional routine outcome monitoring likely makes interpretation easier than referring to norms and clinical severity cutoffs for many distinct measures. Furthermore, increased specificity enhances predictive power and allows BHPs to screen and track other conditions besides depression and anxiety. (It is worth noting that there are no known studies that have looked at the difference in time to administer or ease of interpretation of multidimensional routine outcome monitoring tools vs multiple single-domain measures.)

Two multidimensional routine outcome monitoring tools that cover a comprehensive series of discrete symptom and functional domains are the Treatment Outcome Package¹² and Counseling Center ­Assessment of Psychological Symptoms.¹⁶ These tools, which include subscales beyond general depression and anxiety (eg, sleep, substance misuse, social conflict), take 7 to 10 minutes to complete and provide outcome results across 12 symptom and 8 functional dimensions. As an example, the Treatment Outcome Package has good psychometric qualities (eg, reliability, construct and concurrent validity) for adults,¹² children,^14,19 and adolescents,¹⁹ and can be administered through a secure online data collection portal. The Counseling Center Assessment of Psychological Symptoms has demonstrated high construct validity and good convergent validity.¹⁶ These assessments can be administered in paper or digital (eg, electronic medical record portal, smartphone) format.²⁰

Continue to: CASE SCENARIO

CASE SCENARIO

Ms. W’s physician asked her to go online using her phone and answer the questions in the Treatment Outcome Package. Her results, which she viewed with her physician, were displayed in graph form (FIGURE). Her scores were represented in Z scores normalized to the general population, with “0” representing the general, nontreatment-seeking population average and positive scores representing the number of standard deviations (SDs) more severe than the general population average.

Although this assessment scored Ms. W’s clinically elevated depression as mild, it revealed abnormalities in 3 other domains. Sexual functioning issues represented the most abnormal domain at greater than 3 SDs (more severe than the general population), followed by poor life quality and school/work functioning.

After reviewing Ms. W’s report, her physician decided that pharmacologic management alone (for depression) was not the most appropriate treatment course. Therefore, her physician recommended psychotherapy in addition to the SSRI she was taking. Ms. W agreed to a customized referral for psychotherapy.

Data-driven referrals

When psychotherapy is chosen as a treatment, the individual BHP is an active component of that treatment. Consequently, it is essential to customize referrals to match a patient’s most elevated mental health concerns with a therapist who will most effectively treat those domains. It is rare for a BHP to be skilled in treating every mental health domain.⁹ Multiple studies have shown that BHPs have identifiable treatment skills in specific domains, which physicians should consider when making referrals.^9,21,22 These studies demonstrate the utility of aggregating patient-level routine outcome monitoring data to better understand therapist-level (and ultimately clinic- and system-level) outcomes.

It is essential to customize referrals to match a patient’s most elevated mental health concerns with a therapist who will most effectively treat those domains.

Additionally, recent research has tested this idea prospectively. An RCT funded by the Patient-Centered Outcome Research Institute and published in JAMA Psychiatry showed a significant and positive effect on patient outcomes (ie, reductions in general impairment, impairment involving a patient’s most elevated domain, and global distress) using paired-on outcome data matching vs as-usual matching protocols (eg, therapist self-defined areas of specialty).²² In the RCT, the most effective matching protocol was a combination of eliminating harm and matching the patient on their 3 most problematic domains (the highest match level). These patients ended care as healthy as the general population after 16 weeks of treatment. A random 1-year follow-up assessment from the original RCT showed that most patients who had been matched had maintained their improvement.²³

Continue to: Therefore, a multidimensional routine outcome...

Therefore, a multidimensional routine outcome monitoring tool can be used to identify a BHP’s relative strengths and weaknesses across multiple outcome domains. Within a system of care, a sample of BHPs will possess varying outcome-domain profiles. When a new patient is seeking a referral to a BHP, these profiles (or domain-specific outcome track records) can be used to support paired-on outcome data matching. Specifically, a new patient completes the multidimensional routine outcome monitoring tool at pretreatment, and the results reveal the outcome domains on which the patient is most clinically severe. This pattern of domain-specific severity then can be used to pair the new patient with a BHP who has demonstrated success in addressing the same outcome domain(s). This approach matches a new patient to a BHP with established expertise based on routine outcome monitoring.

Retrospective and prospective studies have found that most BHPs have stable performance in their strengths and weaknesses.^11,21 One study found that assessing BHP performance with their most recent 30 patients can reliably predict future performance with their next 30 patients.²⁴ This predictability in a practitioner’s outcomes suggests report cards that are updated frequently can be utilized to make case assignments within BH or referrals to a specific BHP from primary care.

Making a paired-on outcome data–matched referral

Making customized BH referrals requires access to information about a practitioner’s previous routine outcome monitoring data per clinical domain (eg, suicidality, violence, quality of life) from their most recent patients. Previous research suggests that follow-up data from a minimum of 15 patients is necessary to make a reliable evaluation of a practitioner’s strengths and weaknesses (ie, effectiveness “report card”) per clinical ­domain.²⁴

Previous research suggests that follow-up data from a minimum of 15 patients is necessary to make a reliable evaluation of a practitioner’s strengths and weaknesses.

Few, if any, physicians have access to this level of updated outcome data from their referral network. To facilitate widespread use of paired-on outcome data matching, a new Web system (MatchedTherapists.com) will allow the general public and PCPs to access these grades. As a public service option, this site currently allows for a self-assessment using the Treatment Outcome Package. Pending versions will generate paired-on outcome data grades, and users will receive a list of local therapists available for in-person appointments as well as therapists available for virtual appointments. The paired-on outcome data grades are delivered in school-based letter grades. An “A+,” for example, represents the best matching grade. Users also will be able to sort and filter results for other criteria such as telemedicine, insurance, age, gender, and appointment availability. Currently, there are more than 77,000 therapists listed on the site nationwide. A basic listing is free.

CASE SCENARIO

After Ms. W took the multidimensional routine outcome assessment online, she received a list of therapists rank-ordered by paired-on outcome data grade, with the “A+” matches listed first. Three of the best-matched referrals accepted her insurance and were willing to see her through telemedicine. Therapists with available in-person appointments had a “B” grade. After discussing the options with her physician, Ms. W opted for telehealth counseling with the therapist whose profile she liked best. The therapist and PCP tracked her progress through routine outcome monitoring reporting until all her symptoms became subclinical.

Continue to: The future of a "referral bridge"

In this article, we present a solution to a common issue faced by mental health care patients: failure to benefit meaningfully from mental health treatment. Matching patients to specific BHPs based on effectiveness data regarding the therapist’s strengths and skills can improve patient outcomes and reduce harm. In addition, patients appear to value this approach. A Robert Wood Johnson Foundation–­funded study demonstrated that patients value seeing practitioners who have a track record of successfully treating previous patients with similar issues.^25,26 In many cases, patients indicated they would prioritize this matching process over other factors such as practitioners with a higher number of years of experience or the same demographic characteristics as the patient.^25,26

In many cases, patients indicated they would prioritize this matching process over other factors such as practitioners with a higher number of years of experience.

These findings may represent a new area in the science of health care. Over the past century, major advances in diagnosis and treatment—the 2 primary pillars of health care—have turned the art of medicine into a science. However, the art of making referrals has not advanced commensurately, as there has been little attention focused on the “referral bridge” between these 2 pillars. As the studies reviewed in this paper demonstrate, a referral bridge deserves exploration in all fields of medicine.

CORRESPONDENCE
David R. Kraus, PhD, 1 Speen Street, Framingham, MA 01701; [email protected]

SEATTLE – At least for now, the number of physicians trained to perform Mohs surgery is not only stable but appears to be increasing. New findings show that the number of new fellows offsets the attrition rate and that has been the case for the past 5 years.

Using CMS billing codes as a surrogate, the researchers found that there was a steady increase in the number of physicians who billed from 2015 to 2020. With the exception of 2020, which was the height of the COVID-19 pandemic, the number of times that a specific code was billed for increased on average by 4.7% annually.

“Thus, if the attrition rate remains stable, even with changes in board certification and potential payer eligibility restrictions, the number of physicians will continue to increase,” study author Ji Won Ahn, MD, who specializes in dermatology and Mohs surgery at University of Pittsburgh Medical Center, said at the annual meeting of the American College of Mohs Surgery, where she presented the results.

The growth in the number of Mohs surgeons has been fueled by several factors, including a rising incidence of skin cancer as well as the superior cure rates and cosmetic outcomes with the procedure. Reimbursement has been favorable and training pathways have expanded. A 2019 retrospective study reported that there were 2,240 dermatologists who performed Mohs surgery in the United States, with nearly all of them (94.6%) residing in metropolitan areas.

Dr. Ahn explained that it was important to define the workforce because of several new factors that will be affecting it in the future. “With the establishment of Micrographic Surgery and Dermatologic Oncology [MSDO] board certification that went into effect 2 years ago, potential future payer eligibility restrictions may be coming,” she said. “The adequacy of the Mohs surgery workforce is an important consideration.”

Another issue is that new board certification will be limited to fellowship-trained physicians after the first 5 years. “We wanted to compare these numbers with the fellowship numbers,” she said. “Although fellowship numbers are something that the college potentially has the power to change.”

Dr. Ahn and colleagues used the Centers for Medicare & Medicaid Services database to evaluate the use of the Current Procedural Terminology (CPT) code 17311, which is one of the most common billing codes for Mohs micrographic technique. Looking at data from 2015-2020, they found that there was an annual increase in the number of unique national provider identifiers (NPIs) billing for 17311, at an average rate of 75.6 per year.

The total number of times that 17311 was billed also increased from 2015 to 2019 at an average rate of 4.7% per year but declined in 2020 by 8.4%. “Overall, there was an average of 135 new NPIs that appeared and an average of 59.4 NPIs that stopped billing for 17311,” thus, an attrition rate of 59 surgeons, Dr. Ahn explained.

She emphasized that notably, the number of approved MSDO fellowship spots has remained stable since 2016 and is about 92 to 93 per year. “There are about 135 new surgeons and about two-thirds are new fellowship graduates,” she said.

The researchers were also interested in seeing how saturated each surgeon was and looked at the approximate number of cases that they were handling.

Of the physicians who billed 17311 through CMS, over 26% billed less than 100 times and more than 45% billed less than 200 times, and over 80% billed less than 500 times.

“One might be able to conclude that there might be some potential flexibility depending on the future need for surgeons,” she said.

The study was limited by several factors, one being that the researchers looked only at CPT code 17311 and not other designated codes for Mohs surgery. Other factors such as staff and space limitations were not accounted for since only billing data were used.

Dr. Ahn and her team are going to continue their work, and the next steps are to look at geographic trends and monitor for insurance network eligibility changes. “We are currently doing a workforce survey so we can better understand our current workforce rather than just historical data,” she concluded.

Asked to comment on the results, Vishal Patel, MD, assistant professor of dermatology and director of the cutaneous oncology program at George Washington University, Washington, who was not involved with the study, noted that the increase in the “billing rates of the first stage of Mohs micrographic surgery highlights not only the growing skin cancer epidemic, but also the number of providers who are providing these services. This underscores the importance of standardized training guidelines and board certifications of Mohs micrographic surgeons to assure high levels of patient care and the appropriate use of Mohs micrographic surgery,” he said.

No external funding of the study was reported. Dr. Ahn reported no relevant financial relationships. Dr. Patel is a consultant for Sanofi, Regeneron, and Almirall.
 

A version of this article originally appeared on Medscape.com.

SEATTLE – At least for now, the number of physicians trained to perform Mohs surgery is not only stable but appears to be increasing. New findings show that the number of new fellows offsets the attrition rate and that has been the case for the past 5 years.

Using CMS billing codes as a surrogate, the researchers found that there was a steady increase in the number of physicians who billed from 2015 to 2020. With the exception of 2020, which was the height of the COVID-19 pandemic, the number of times that a specific code was billed for increased on average by 4.7% annually.

“Thus, if the attrition rate remains stable, even with changes in board certification and potential payer eligibility restrictions, the number of physicians will continue to increase,” study author Ji Won Ahn, MD, who specializes in dermatology and Mohs surgery at University of Pittsburgh Medical Center, said at the annual meeting of the American College of Mohs Surgery, where she presented the results.

The growth in the number of Mohs surgeons has been fueled by several factors, including a rising incidence of skin cancer as well as the superior cure rates and cosmetic outcomes with the procedure. Reimbursement has been favorable and training pathways have expanded. A 2019 retrospective study reported that there were 2,240 dermatologists who performed Mohs surgery in the United States, with nearly all of them (94.6%) residing in metropolitan areas.

Dr. Ahn explained that it was important to define the workforce because of several new factors that will be affecting it in the future. “With the establishment of Micrographic Surgery and Dermatologic Oncology [MSDO] board certification that went into effect 2 years ago, potential future payer eligibility restrictions may be coming,” she said. “The adequacy of the Mohs surgery workforce is an important consideration.”

Another issue is that new board certification will be limited to fellowship-trained physicians after the first 5 years. “We wanted to compare these numbers with the fellowship numbers,” she said. “Although fellowship numbers are something that the college potentially has the power to change.”

Dr. Ahn and colleagues used the Centers for Medicare & Medicaid Services database to evaluate the use of the Current Procedural Terminology (CPT) code 17311, which is one of the most common billing codes for Mohs micrographic technique. Looking at data from 2015-2020, they found that there was an annual increase in the number of unique national provider identifiers (NPIs) billing for 17311, at an average rate of 75.6 per year.

The total number of times that 17311 was billed also increased from 2015 to 2019 at an average rate of 4.7% per year but declined in 2020 by 8.4%. “Overall, there was an average of 135 new NPIs that appeared and an average of 59.4 NPIs that stopped billing for 17311,” thus, an attrition rate of 59 surgeons, Dr. Ahn explained.

She emphasized that notably, the number of approved MSDO fellowship spots has remained stable since 2016 and is about 92 to 93 per year. “There are about 135 new surgeons and about two-thirds are new fellowship graduates,” she said.

The researchers were also interested in seeing how saturated each surgeon was and looked at the approximate number of cases that they were handling.

Of the physicians who billed 17311 through CMS, over 26% billed less than 100 times and more than 45% billed less than 200 times, and over 80% billed less than 500 times.

“One might be able to conclude that there might be some potential flexibility depending on the future need for surgeons,” she said.

The study was limited by several factors, one being that the researchers looked only at CPT code 17311 and not other designated codes for Mohs surgery. Other factors such as staff and space limitations were not accounted for since only billing data were used.

Dr. Ahn and her team are going to continue their work, and the next steps are to look at geographic trends and monitor for insurance network eligibility changes. “We are currently doing a workforce survey so we can better understand our current workforce rather than just historical data,” she concluded.

Asked to comment on the results, Vishal Patel, MD, assistant professor of dermatology and director of the cutaneous oncology program at George Washington University, Washington, who was not involved with the study, noted that the increase in the “billing rates of the first stage of Mohs micrographic surgery highlights not only the growing skin cancer epidemic, but also the number of providers who are providing these services. This underscores the importance of standardized training guidelines and board certifications of Mohs micrographic surgeons to assure high levels of patient care and the appropriate use of Mohs micrographic surgery,” he said.

No external funding of the study was reported. Dr. Ahn reported no relevant financial relationships. Dr. Patel is a consultant for Sanofi, Regeneron, and Almirall.
 

A version of this article originally appeared on Medscape.com.

SEATTLE – At least for now, the number of physicians trained to perform Mohs surgery is not only stable but appears to be increasing. New findings show that the number of new fellows offsets the attrition rate and that has been the case for the past 5 years.

Using CMS billing codes as a surrogate, the researchers found that there was a steady increase in the number of physicians who billed from 2015 to 2020. With the exception of 2020, which was the height of the COVID-19 pandemic, the number of times that a specific code was billed for increased on average by 4.7% annually.

“Thus, if the attrition rate remains stable, even with changes in board certification and potential payer eligibility restrictions, the number of physicians will continue to increase,” study author Ji Won Ahn, MD, who specializes in dermatology and Mohs surgery at University of Pittsburgh Medical Center, said at the annual meeting of the American College of Mohs Surgery, where she presented the results.

The growth in the number of Mohs surgeons has been fueled by several factors, including a rising incidence of skin cancer as well as the superior cure rates and cosmetic outcomes with the procedure. Reimbursement has been favorable and training pathways have expanded. A 2019 retrospective study reported that there were 2,240 dermatologists who performed Mohs surgery in the United States, with nearly all of them (94.6%) residing in metropolitan areas.

Dr. Ahn explained that it was important to define the workforce because of several new factors that will be affecting it in the future. “With the establishment of Micrographic Surgery and Dermatologic Oncology [MSDO] board certification that went into effect 2 years ago, potential future payer eligibility restrictions may be coming,” she said. “The adequacy of the Mohs surgery workforce is an important consideration.”

Another issue is that new board certification will be limited to fellowship-trained physicians after the first 5 years. “We wanted to compare these numbers with the fellowship numbers,” she said. “Although fellowship numbers are something that the college potentially has the power to change.”

Dr. Ahn and colleagues used the Centers for Medicare & Medicaid Services database to evaluate the use of the Current Procedural Terminology (CPT) code 17311, which is one of the most common billing codes for Mohs micrographic technique. Looking at data from 2015-2020, they found that there was an annual increase in the number of unique national provider identifiers (NPIs) billing for 17311, at an average rate of 75.6 per year.

The total number of times that 17311 was billed also increased from 2015 to 2019 at an average rate of 4.7% per year but declined in 2020 by 8.4%. “Overall, there was an average of 135 new NPIs that appeared and an average of 59.4 NPIs that stopped billing for 17311,” thus, an attrition rate of 59 surgeons, Dr. Ahn explained.

She emphasized that notably, the number of approved MSDO fellowship spots has remained stable since 2016 and is about 92 to 93 per year. “There are about 135 new surgeons and about two-thirds are new fellowship graduates,” she said.

The researchers were also interested in seeing how saturated each surgeon was and looked at the approximate number of cases that they were handling.

Of the physicians who billed 17311 through CMS, over 26% billed less than 100 times and more than 45% billed less than 200 times, and over 80% billed less than 500 times.

“One might be able to conclude that there might be some potential flexibility depending on the future need for surgeons,” she said.

The study was limited by several factors, one being that the researchers looked only at CPT code 17311 and not other designated codes for Mohs surgery. Other factors such as staff and space limitations were not accounted for since only billing data were used.

Dr. Ahn and her team are going to continue their work, and the next steps are to look at geographic trends and monitor for insurance network eligibility changes. “We are currently doing a workforce survey so we can better understand our current workforce rather than just historical data,” she concluded.

Asked to comment on the results, Vishal Patel, MD, assistant professor of dermatology and director of the cutaneous oncology program at George Washington University, Washington, who was not involved with the study, noted that the increase in the “billing rates of the first stage of Mohs micrographic surgery highlights not only the growing skin cancer epidemic, but also the number of providers who are providing these services. This underscores the importance of standardized training guidelines and board certifications of Mohs micrographic surgeons to assure high levels of patient care and the appropriate use of Mohs micrographic surgery,” he said.

No external funding of the study was reported. Dr. Ahn reported no relevant financial relationships. Dr. Patel is a consultant for Sanofi, Regeneron, and Almirall.
 

A version of this article originally appeared on Medscape.com.

Clinical advances in myasthenia gravis from the 2023 American Academy of Neurology (AAN) Annual Meeting include the association between fatigue and disease severity and promising results from three ongoing trials of novel therapies, as reported by Dr Nicholas Silvestri, from the University at Buffalo, Buffalo, New York. 

Dr Silvestri begins by discussing a study of autoantibodies in patients with seronegative disease, which highlighted the potential for impaired B-cell tolerance, and goes on to examine research underscoring the association between fatigue and disease severity, as well as anxiety and depression. 

Moving on to novel therapies, Dr Silvestri reviews a combined analysis of three trials of rozanolixizumab, which demonstrated the drug's encouraging efficacy and favorable safety profile. 

Next, he turns to the ADAPT+ trial, which showed that efgartigimod continued to have an improved clinical response after patients rolled over from the initial ADAPT trial to ADAPT+, with no new safety signals apparent. 

Finally, Dr Silvestri looks at data from the postmarketing registry of eculizumab, which revealed how a significant proportion of patients were able discontinue or reduce their other medications once they started the drug. 

--

Nicholas J. Silvestri, MD, Associate Professor, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York 

Nicholas J. Silvestri, MD, has disclosed the following relevant financial relationships: 

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: argenx; Alexion; Immunovant; UCB 

Serve(d) as a speaker or a member of a speakers bureau for: argenx; Alexion 

Clinical advances in myasthenia gravis from the 2023 American Academy of Neurology (AAN) Annual Meeting include the association between fatigue and disease severity and promising results from three ongoing trials of novel therapies, as reported by Dr Nicholas Silvestri, from the University at Buffalo, Buffalo, New York. 

Dr Silvestri begins by discussing a study of autoantibodies in patients with seronegative disease, which highlighted the potential for impaired B-cell tolerance, and goes on to examine research underscoring the association between fatigue and disease severity, as well as anxiety and depression. 

Moving on to novel therapies, Dr Silvestri reviews a combined analysis of three trials of rozanolixizumab, which demonstrated the drug's encouraging efficacy and favorable safety profile. 

Next, he turns to the ADAPT+ trial, which showed that efgartigimod continued to have an improved clinical response after patients rolled over from the initial ADAPT trial to ADAPT+, with no new safety signals apparent. 

Finally, Dr Silvestri looks at data from the postmarketing registry of eculizumab, which revealed how a significant proportion of patients were able discontinue or reduce their other medications once they started the drug. 

--

Nicholas J. Silvestri, MD, Associate Professor, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York 

Nicholas J. Silvestri, MD, has disclosed the following relevant financial relationships: 

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: argenx; Alexion; Immunovant; UCB 

Serve(d) as a speaker or a member of a speakers bureau for: argenx; Alexion 

Clinical advances in myasthenia gravis from the 2023 American Academy of Neurology (AAN) Annual Meeting include the association between fatigue and disease severity and promising results from three ongoing trials of novel therapies, as reported by Dr Nicholas Silvestri, from the University at Buffalo, Buffalo, New York. 

Dr Silvestri begins by discussing a study of autoantibodies in patients with seronegative disease, which highlighted the potential for impaired B-cell tolerance, and goes on to examine research underscoring the association between fatigue and disease severity, as well as anxiety and depression. 

Moving on to novel therapies, Dr Silvestri reviews a combined analysis of three trials of rozanolixizumab, which demonstrated the drug's encouraging efficacy and favorable safety profile. 

Next, he turns to the ADAPT+ trial, which showed that efgartigimod continued to have an improved clinical response after patients rolled over from the initial ADAPT trial to ADAPT+, with no new safety signals apparent. 

Finally, Dr Silvestri looks at data from the postmarketing registry of eculizumab, which revealed how a significant proportion of patients were able discontinue or reduce their other medications once they started the drug. 

--

Nicholas J. Silvestri, MD, Associate Professor, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York 

Nicholas J. Silvestri, MD, has disclosed the following relevant financial relationships: 

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: argenx; Alexion; Immunovant; UCB 

Serve(d) as a speaker or a member of a speakers bureau for: argenx; Alexion 

Adding neoadjuvant atezolizumab to chemotherapy was associated with a significantly improved response in patients with early-stage triple-negative breast cancer, based on final data from a randomized trial.

The IMpassion031 trial showed significant improvement in pathological complete response (pCR) with the addition of atezolizumab to chemotherapy, as well as an acceptable safety profile, said Carlos H. Barrios, MD, of the Latin American Cooperative Oncology Group, Oncoclinicas, in Porto Allegre, Brazil, at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress. Those findings were published in the Lancet in 2020.

Heidi Splete/MDedge News

Dr. Barrios reported data from a final analysis of the IMpassion031 trial, with data on event-free survival (EFS), disease-free survival (DFS) and overall survival (OS) in the intent-to-treat (ITT) and PD-L1–positive populations.

In the study, patients with early triple-negative breast cancer (eTNBC) and a primary tumor greater than 2 cm were randomized to 840 mg of atezolizumab once every 2 weeks plus a neoadjuvant chemotherapy regimen of nab-paclitaxel 125 mg/m² once weekly for 12 weeks, followed by doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m² once every 2 weeks for 8 weeks. A total of 333 patients were randomized (165 atezolizumab and 168 placebo). Patients were stratified by stage II versus stage III, and by status of PD-L1, a protein that can predict treatment response (PD-L1 less than 1% vs. 1% or higher).

The primary endpoints (previously reported) were pathological complete response (pCR) in the ITT and PD-L1 populations. After a median follow-up of 39 months, the pCR was 58% in patients treated with atezolizumab versus 41% in those treated with neoadjuvant chemotherapy alone (P = .0044) in the ITT population, Dr. Barrios said. The added benefit from atezolizumab occurred regardless of the status of PD-L1.

Dr. Barrios reported the secondary outcomes of EFS, DFS, and OS in the intent-to-treat and PD-L1–positive populations. “This is a descriptive analysis, with no statistical comparison,” he emphasized.

The 2-year data on EFS, DFS, and OS consistently favored atezolizumab across key clinical subgroups, Dr. Barrios said. In the ITT population, 2-year EFS, DFS, and OS was 85%, 87%, and 95%, respectively, in the atezolizumab group and 80%, 83%, and 90%, respectively, in the placebo group. The results were similar, irrespective of PD-L1 status.

In the PD-L1–positive population, 2-year EFS, DFS, and OS was 89%, 91%, and 95%, respectively, in atezolizumab patients and 80%, 87%, and 91% in placebo patients.

Among patients without pCR at the time of surgery, 14 of 70 patients (20%) in the atezolizumab group and 33 of 99 patients (33%) in the placebo group received additional adjuvant systemic therapy. The most common adjunctive therapy was capecitabine.

As for safety, no new safety signals or treatment-related deaths were observed in the study. Overall, 70% of atezolizumab patients and 62% of placebo patients experienced grade 3 or 4 adverse events (AEs); 59% and 54% of which were treatment related. A total of 1% of patients in each group experienced grade 5 AEs. A total of 25% of atezolizumab patients and 20% of placebo patients experienced AEs leading to treatment discontinuation.

In a further exploratory analysis, pCR was highly predictive of long-term outcomes. Exploratory analysis of circulating tumor DNA (ctDNA) showed clearance in 89% of atezolizumab patients and 86% of placebo patients by the time of surgery.

Looking at the relationship between ctDNA, DFS, and OS, positive ctDNA was associated with a worse prognosis following surgery. As demonstrated in previous studies, pCR patients with negative ctDNA had the best DFS and OS. “In non-pCR patients with positive ctDNA, a numerical trend suggests improved overall survival with atezolizumab,” although the caveat is the very small numbers, Dr. Barrios said.

More research is needed, but in the final analysis, the significant pCR benefit seen with the addition of atezolizumab to chemotherapy for eTNBC translated into numerically improved EFS, DFS and OS, said Dr. Barrios. Additionally, “we should further analyze ctDNA to help select patients for further therapy.”

In a question-and-answer session, Dr. Barrios was asked how the results compared with other studies.

“We should not overinterpret the results,” he said. However, “what the IMpassion031 study shows is consistency; the results are aligned with previous studies addressing the same question of introducing immunotherapy,” in the patient population. Although the numbers in the IMpassion031 study did not reach statistical significance, it is important to recognize that they reflect previous research.

“In my opinion, looking at the whole field, immunotherapy is something we need to consider as part of the treatment of these patients,” said Dr. Barrios. However, more research is needed to better identify which patients do and do not need chemotherapy.
 

Phase 2 data show increased response with added atezolizumab for PD-L1–negative patients

In a second study known as ABSCG-52/ATHENE, researchers evaluated neoadjuvant atezolizumab in combination with dual HER2 blockade plus epirubicin for the treatment of patients with early HER2-positive breast cancer.

Heidi Splete/MDedge News

For most of these patients, the current standard of care is neoadjuvant dual HER2 blockade with trastuzumab (T) and pertuzumab (P) plus poly-chemotherapy, said Gabriel Rinnerthaler, MD, of the Salzburg (Austria) Cancer Research Institute, said in his presentation at the meeting. However, de-escalation of chemotherapy has been a major focus of research in recent years, and more research is needed on a combination of anthracyclines, such as epirubicin and idarubicin, and immune-checkpoint modulators.

In the phase 2 study, the researchers randomized patients with previously untreated, histologically confirmed HER2-positive early breast cancer (defined as a clinical prognostic stage cT1c–4a-d, N0-3, M0) in a 1:1 ratio to two 3-weekly cycles of a chemotherapy-free induction phase (part 1) with TP plus 1,200 mg atezolizumab (TP-A) or TP alone.

“We hypothesized that the additive effect of immune checkpoint inhibitors plus anti-HER2 therapy and chemotherapy would not be linear,” he said.

At the end of this period, all patients underwent four cycles of TP-A in combination with epirubicin (part 2). The primary endpoint was pCR (defined as absence of invasive cancer in the breast and axillary nodes, or ypT0/Tis ypN0) in the overall study population, and a pCR of 40% was considered a positive result.

A total of 29 patients were randomized to TP-A and 29 to TP alone in nine treatment centers in Austria. The study population ranged from 33 to 82 years, with a median age of 57 years. Most patients (72.4%) had hormone receptor (HR)–positive tumors; a total of 45 patients had stage IIA cancer, and 13 had stage IIB.

The primary endpoint of pCR occurred in 35 patients overall (60.3%). In a univariate analysis, the response rates were lower in HR-positive patients, in premenopausal patients, and in histologies other than NST (invasive carcinoma of no special type), Dr. Rinnerthaler said, but none of the differences were statistically significant, likely because of the small numbers in each group.

In an exploratory analysis of the ITT population with available PD-L1 data, the pCR was 69.2% for PD-L1–negative patients and 55.2% for PD-L1–positive patients.

“We observed the highest pCR rates in PD-L1–negative patients treated in the TP-A group and the lowest in PD-L1–positive patients treated with TP alone,” Dr. Rinnerthaler said.

No new safety concerns were observed during the study, Dr. Rinnerthaler noted. AEs of grade 3 or higher occurred in 17 patients (29.3%), including 9 in the TP-A group and 8 in the TP group. The most common AEs in both groups were nausea, diarrhea, and fatigue. No AEs of special interest of grade 3 or higher (defined as immune-related AEs, cardiac disorders, or infusion-related reactions) were observed.

The study findings were limited by the small sample size, but the resulting pCR rate of 60.3% was higher than the predefined threshold of 40% and supports additional research, said Dr. Rinnerthaler.

“For HER2-positive early breast cancer, a neoadjuvant chemotherapy de-escalation immunotherapy regimen with trastuzumab, pertuzumab, atezolizumab, and epirubicin is highly effective and safe and merits further investigation,” he concluded.

During a question-and-answer session, Dr. Rinnerthaler was asked why pCR increased in PD-L1 negative patients.

Previous data have shown that PD-L1 is up-regulated in certain tumors, and may serve as a surrogate for sensitivity, he said. In previous studies the additional effect of atezolizumab was seen in a PD-L1–negative group.

Dr. Rinnerthaler said he hopes to clarify this question when his research team reviews biopsy data from baseline and after the induction phase.
 

Defining response is key to de-escalation

In the IMpassion031 trial, “what we saw is a tendency to better outcomes for those patients who received atezolizumab,” said Matteo Lambertini, MD, of the University of Genova (Italy), who served as discussant for the two studies. The IMpassion031 study raises the question of where we are in the use of immuno-oncology for eTNBC. The study is now one of five neoadjuvant trials in this population.

Heidi Splete/MDedge News

Dr. Lambertini cited the KEYNOTE-522 study, which showed significant results in EFS. However, sample sizes and statistical design were different between these studies. “I think we need large studies of data in the adjuvant and postneoadjuvant setting for patients with triple-negative breast cancer.”

Postneoadjuvant considerations from the IMpassion031 trial showed good outcomes with no additional benefit of an immune checkpoint inhibitors.

For those patients with a pCR, it is definitely time to de-escalate treatment,” he said. In patients without pCR, escalation is needed, but an improved definition of pCR is also needed.

With regard to the ATHENE study, “it may be considered a positive study because the threshold of 40% was reached,” he said. The question is what is the optimum chemotherapy backbone. There appears to be no added benefit to adding an immune checkpoint inhibitor.

There are needs for defining the role of immunotherapy in HER2-positive breast cancer and more biomarker research to inform patient selection and study design, he said.

Finally, “I am not sure that the addition of an immune checkpoint inhibitor can be considered a de-escalation,” he noted.

IMpassion031 was supported by F. Hoffmann–La Roche. Dr. Barrio disclosed financial relationships with numerous companies. ABSCG-52/ATHENE was supported by the Austrian Breast and Colorectal Cancer Study Group and Roche Austria. Dr. Rinnerthaler disclosed relationships with multiple companies including Amgen, Daiichi Sankyo, Lilly, Gilead, MSD, Novartis, Pfizer, Roche, Seagen, and Pierre Fabre. Dr. Lambertini disclosed relationships with multiple companies including Roche, Novartis, AstraZeneca, Lilly, Exact Sciences, Pfizer, MSD, Seagen, Gilead, Takeda, Sandoz, Ipsen, Libbs, Knight, and Daiichi Sankyo.

Adding neoadjuvant atezolizumab to chemotherapy was associated with a significantly improved response in patients with early-stage triple-negative breast cancer, based on final data from a randomized trial.

The IMpassion031 trial showed significant improvement in pathological complete response (pCR) with the addition of atezolizumab to chemotherapy, as well as an acceptable safety profile, said Carlos H. Barrios, MD, of the Latin American Cooperative Oncology Group, Oncoclinicas, in Porto Allegre, Brazil, at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress. Those findings were published in the Lancet in 2020.

Heidi Splete/MDedge News

Dr. Barrios reported data from a final analysis of the IMpassion031 trial, with data on event-free survival (EFS), disease-free survival (DFS) and overall survival (OS) in the intent-to-treat (ITT) and PD-L1–positive populations.

In the study, patients with early triple-negative breast cancer (eTNBC) and a primary tumor greater than 2 cm were randomized to 840 mg of atezolizumab once every 2 weeks plus a neoadjuvant chemotherapy regimen of nab-paclitaxel 125 mg/m² once weekly for 12 weeks, followed by doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m² once every 2 weeks for 8 weeks. A total of 333 patients were randomized (165 atezolizumab and 168 placebo). Patients were stratified by stage II versus stage III, and by status of PD-L1, a protein that can predict treatment response (PD-L1 less than 1% vs. 1% or higher).

The primary endpoints (previously reported) were pathological complete response (pCR) in the ITT and PD-L1 populations. After a median follow-up of 39 months, the pCR was 58% in patients treated with atezolizumab versus 41% in those treated with neoadjuvant chemotherapy alone (P = .0044) in the ITT population, Dr. Barrios said. The added benefit from atezolizumab occurred regardless of the status of PD-L1.

Dr. Barrios reported the secondary outcomes of EFS, DFS, and OS in the intent-to-treat and PD-L1–positive populations. “This is a descriptive analysis, with no statistical comparison,” he emphasized.

The 2-year data on EFS, DFS, and OS consistently favored atezolizumab across key clinical subgroups, Dr. Barrios said. In the ITT population, 2-year EFS, DFS, and OS was 85%, 87%, and 95%, respectively, in the atezolizumab group and 80%, 83%, and 90%, respectively, in the placebo group. The results were similar, irrespective of PD-L1 status.

In the PD-L1–positive population, 2-year EFS, DFS, and OS was 89%, 91%, and 95%, respectively, in atezolizumab patients and 80%, 87%, and 91% in placebo patients.

Among patients without pCR at the time of surgery, 14 of 70 patients (20%) in the atezolizumab group and 33 of 99 patients (33%) in the placebo group received additional adjuvant systemic therapy. The most common adjunctive therapy was capecitabine.

As for safety, no new safety signals or treatment-related deaths were observed in the study. Overall, 70% of atezolizumab patients and 62% of placebo patients experienced grade 3 or 4 adverse events (AEs); 59% and 54% of which were treatment related. A total of 1% of patients in each group experienced grade 5 AEs. A total of 25% of atezolizumab patients and 20% of placebo patients experienced AEs leading to treatment discontinuation.

In a further exploratory analysis, pCR was highly predictive of long-term outcomes. Exploratory analysis of circulating tumor DNA (ctDNA) showed clearance in 89% of atezolizumab patients and 86% of placebo patients by the time of surgery.

Looking at the relationship between ctDNA, DFS, and OS, positive ctDNA was associated with a worse prognosis following surgery. As demonstrated in previous studies, pCR patients with negative ctDNA had the best DFS and OS. “In non-pCR patients with positive ctDNA, a numerical trend suggests improved overall survival with atezolizumab,” although the caveat is the very small numbers, Dr. Barrios said.

More research is needed, but in the final analysis, the significant pCR benefit seen with the addition of atezolizumab to chemotherapy for eTNBC translated into numerically improved EFS, DFS and OS, said Dr. Barrios. Additionally, “we should further analyze ctDNA to help select patients for further therapy.”

In a question-and-answer session, Dr. Barrios was asked how the results compared with other studies.

“We should not overinterpret the results,” he said. However, “what the IMpassion031 study shows is consistency; the results are aligned with previous studies addressing the same question of introducing immunotherapy,” in the patient population. Although the numbers in the IMpassion031 study did not reach statistical significance, it is important to recognize that they reflect previous research.

“In my opinion, looking at the whole field, immunotherapy is something we need to consider as part of the treatment of these patients,” said Dr. Barrios. However, more research is needed to better identify which patients do and do not need chemotherapy.
 

Phase 2 data show increased response with added atezolizumab for PD-L1–negative patients

In a second study known as ABSCG-52/ATHENE, researchers evaluated neoadjuvant atezolizumab in combination with dual HER2 blockade plus epirubicin for the treatment of patients with early HER2-positive breast cancer.

Heidi Splete/MDedge News

For most of these patients, the current standard of care is neoadjuvant dual HER2 blockade with trastuzumab (T) and pertuzumab (P) plus poly-chemotherapy, said Gabriel Rinnerthaler, MD, of the Salzburg (Austria) Cancer Research Institute, said in his presentation at the meeting. However, de-escalation of chemotherapy has been a major focus of research in recent years, and more research is needed on a combination of anthracyclines, such as epirubicin and idarubicin, and immune-checkpoint modulators.

In the phase 2 study, the researchers randomized patients with previously untreated, histologically confirmed HER2-positive early breast cancer (defined as a clinical prognostic stage cT1c–4a-d, N0-3, M0) in a 1:1 ratio to two 3-weekly cycles of a chemotherapy-free induction phase (part 1) with TP plus 1,200 mg atezolizumab (TP-A) or TP alone.

“We hypothesized that the additive effect of immune checkpoint inhibitors plus anti-HER2 therapy and chemotherapy would not be linear,” he said.

At the end of this period, all patients underwent four cycles of TP-A in combination with epirubicin (part 2). The primary endpoint was pCR (defined as absence of invasive cancer in the breast and axillary nodes, or ypT0/Tis ypN0) in the overall study population, and a pCR of 40% was considered a positive result.

A total of 29 patients were randomized to TP-A and 29 to TP alone in nine treatment centers in Austria. The study population ranged from 33 to 82 years, with a median age of 57 years. Most patients (72.4%) had hormone receptor (HR)–positive tumors; a total of 45 patients had stage IIA cancer, and 13 had stage IIB.

The primary endpoint of pCR occurred in 35 patients overall (60.3%). In a univariate analysis, the response rates were lower in HR-positive patients, in premenopausal patients, and in histologies other than NST (invasive carcinoma of no special type), Dr. Rinnerthaler said, but none of the differences were statistically significant, likely because of the small numbers in each group.

In an exploratory analysis of the ITT population with available PD-L1 data, the pCR was 69.2% for PD-L1–negative patients and 55.2% for PD-L1–positive patients.

“We observed the highest pCR rates in PD-L1–negative patients treated in the TP-A group and the lowest in PD-L1–positive patients treated with TP alone,” Dr. Rinnerthaler said.

No new safety concerns were observed during the study, Dr. Rinnerthaler noted. AEs of grade 3 or higher occurred in 17 patients (29.3%), including 9 in the TP-A group and 8 in the TP group. The most common AEs in both groups were nausea, diarrhea, and fatigue. No AEs of special interest of grade 3 or higher (defined as immune-related AEs, cardiac disorders, or infusion-related reactions) were observed.

The study findings were limited by the small sample size, but the resulting pCR rate of 60.3% was higher than the predefined threshold of 40% and supports additional research, said Dr. Rinnerthaler.

“For HER2-positive early breast cancer, a neoadjuvant chemotherapy de-escalation immunotherapy regimen with trastuzumab, pertuzumab, atezolizumab, and epirubicin is highly effective and safe and merits further investigation,” he concluded.

During a question-and-answer session, Dr. Rinnerthaler was asked why pCR increased in PD-L1 negative patients.

Previous data have shown that PD-L1 is up-regulated in certain tumors, and may serve as a surrogate for sensitivity, he said. In previous studies the additional effect of atezolizumab was seen in a PD-L1–negative group.

Dr. Rinnerthaler said he hopes to clarify this question when his research team reviews biopsy data from baseline and after the induction phase.
 

Defining response is key to de-escalation

In the IMpassion031 trial, “what we saw is a tendency to better outcomes for those patients who received atezolizumab,” said Matteo Lambertini, MD, of the University of Genova (Italy), who served as discussant for the two studies. The IMpassion031 study raises the question of where we are in the use of immuno-oncology for eTNBC. The study is now one of five neoadjuvant trials in this population.

Heidi Splete/MDedge News

Dr. Lambertini cited the KEYNOTE-522 study, which showed significant results in EFS. However, sample sizes and statistical design were different between these studies. “I think we need large studies of data in the adjuvant and postneoadjuvant setting for patients with triple-negative breast cancer.”

Postneoadjuvant considerations from the IMpassion031 trial showed good outcomes with no additional benefit of an immune checkpoint inhibitors.

For those patients with a pCR, it is definitely time to de-escalate treatment,” he said. In patients without pCR, escalation is needed, but an improved definition of pCR is also needed.

With regard to the ATHENE study, “it may be considered a positive study because the threshold of 40% was reached,” he said. The question is what is the optimum chemotherapy backbone. There appears to be no added benefit to adding an immune checkpoint inhibitor.

There are needs for defining the role of immunotherapy in HER2-positive breast cancer and more biomarker research to inform patient selection and study design, he said.

Finally, “I am not sure that the addition of an immune checkpoint inhibitor can be considered a de-escalation,” he noted.

IMpassion031 was supported by F. Hoffmann–La Roche. Dr. Barrio disclosed financial relationships with numerous companies. ABSCG-52/ATHENE was supported by the Austrian Breast and Colorectal Cancer Study Group and Roche Austria. Dr. Rinnerthaler disclosed relationships with multiple companies including Amgen, Daiichi Sankyo, Lilly, Gilead, MSD, Novartis, Pfizer, Roche, Seagen, and Pierre Fabre. Dr. Lambertini disclosed relationships with multiple companies including Roche, Novartis, AstraZeneca, Lilly, Exact Sciences, Pfizer, MSD, Seagen, Gilead, Takeda, Sandoz, Ipsen, Libbs, Knight, and Daiichi Sankyo.

Adding neoadjuvant atezolizumab to chemotherapy was associated with a significantly improved response in patients with early-stage triple-negative breast cancer, based on final data from a randomized trial.

The IMpassion031 trial showed significant improvement in pathological complete response (pCR) with the addition of atezolizumab to chemotherapy, as well as an acceptable safety profile, said Carlos H. Barrios, MD, of the Latin American Cooperative Oncology Group, Oncoclinicas, in Porto Allegre, Brazil, at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress. Those findings were published in the Lancet in 2020.

Heidi Splete/MDedge News

Dr. Barrios reported data from a final analysis of the IMpassion031 trial, with data on event-free survival (EFS), disease-free survival (DFS) and overall survival (OS) in the intent-to-treat (ITT) and PD-L1–positive populations.

In the study, patients with early triple-negative breast cancer (eTNBC) and a primary tumor greater than 2 cm were randomized to 840 mg of atezolizumab once every 2 weeks plus a neoadjuvant chemotherapy regimen of nab-paclitaxel 125 mg/m² once weekly for 12 weeks, followed by doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m² once every 2 weeks for 8 weeks. A total of 333 patients were randomized (165 atezolizumab and 168 placebo). Patients were stratified by stage II versus stage III, and by status of PD-L1, a protein that can predict treatment response (PD-L1 less than 1% vs. 1% or higher).

The primary endpoints (previously reported) were pathological complete response (pCR) in the ITT and PD-L1 populations. After a median follow-up of 39 months, the pCR was 58% in patients treated with atezolizumab versus 41% in those treated with neoadjuvant chemotherapy alone (P = .0044) in the ITT population, Dr. Barrios said. The added benefit from atezolizumab occurred regardless of the status of PD-L1.

Dr. Barrios reported the secondary outcomes of EFS, DFS, and OS in the intent-to-treat and PD-L1–positive populations. “This is a descriptive analysis, with no statistical comparison,” he emphasized.

The 2-year data on EFS, DFS, and OS consistently favored atezolizumab across key clinical subgroups, Dr. Barrios said. In the ITT population, 2-year EFS, DFS, and OS was 85%, 87%, and 95%, respectively, in the atezolizumab group and 80%, 83%, and 90%, respectively, in the placebo group. The results were similar, irrespective of PD-L1 status.

In the PD-L1–positive population, 2-year EFS, DFS, and OS was 89%, 91%, and 95%, respectively, in atezolizumab patients and 80%, 87%, and 91% in placebo patients.

Among patients without pCR at the time of surgery, 14 of 70 patients (20%) in the atezolizumab group and 33 of 99 patients (33%) in the placebo group received additional adjuvant systemic therapy. The most common adjunctive therapy was capecitabine.

As for safety, no new safety signals or treatment-related deaths were observed in the study. Overall, 70% of atezolizumab patients and 62% of placebo patients experienced grade 3 or 4 adverse events (AEs); 59% and 54% of which were treatment related. A total of 1% of patients in each group experienced grade 5 AEs. A total of 25% of atezolizumab patients and 20% of placebo patients experienced AEs leading to treatment discontinuation.

In a further exploratory analysis, pCR was highly predictive of long-term outcomes. Exploratory analysis of circulating tumor DNA (ctDNA) showed clearance in 89% of atezolizumab patients and 86% of placebo patients by the time of surgery.

Looking at the relationship between ctDNA, DFS, and OS, positive ctDNA was associated with a worse prognosis following surgery. As demonstrated in previous studies, pCR patients with negative ctDNA had the best DFS and OS. “In non-pCR patients with positive ctDNA, a numerical trend suggests improved overall survival with atezolizumab,” although the caveat is the very small numbers, Dr. Barrios said.

More research is needed, but in the final analysis, the significant pCR benefit seen with the addition of atezolizumab to chemotherapy for eTNBC translated into numerically improved EFS, DFS and OS, said Dr. Barrios. Additionally, “we should further analyze ctDNA to help select patients for further therapy.”

In a question-and-answer session, Dr. Barrios was asked how the results compared with other studies.

“We should not overinterpret the results,” he said. However, “what the IMpassion031 study shows is consistency; the results are aligned with previous studies addressing the same question of introducing immunotherapy,” in the patient population. Although the numbers in the IMpassion031 study did not reach statistical significance, it is important to recognize that they reflect previous research.

“In my opinion, looking at the whole field, immunotherapy is something we need to consider as part of the treatment of these patients,” said Dr. Barrios. However, more research is needed to better identify which patients do and do not need chemotherapy.
 

Phase 2 data show increased response with added atezolizumab for PD-L1–negative patients

In a second study known as ABSCG-52/ATHENE, researchers evaluated neoadjuvant atezolizumab in combination with dual HER2 blockade plus epirubicin for the treatment of patients with early HER2-positive breast cancer.

Heidi Splete/MDedge News

For most of these patients, the current standard of care is neoadjuvant dual HER2 blockade with trastuzumab (T) and pertuzumab (P) plus poly-chemotherapy, said Gabriel Rinnerthaler, MD, of the Salzburg (Austria) Cancer Research Institute, said in his presentation at the meeting. However, de-escalation of chemotherapy has been a major focus of research in recent years, and more research is needed on a combination of anthracyclines, such as epirubicin and idarubicin, and immune-checkpoint modulators.

In the phase 2 study, the researchers randomized patients with previously untreated, histologically confirmed HER2-positive early breast cancer (defined as a clinical prognostic stage cT1c–4a-d, N0-3, M0) in a 1:1 ratio to two 3-weekly cycles of a chemotherapy-free induction phase (part 1) with TP plus 1,200 mg atezolizumab (TP-A) or TP alone.

“We hypothesized that the additive effect of immune checkpoint inhibitors plus anti-HER2 therapy and chemotherapy would not be linear,” he said.

At the end of this period, all patients underwent four cycles of TP-A in combination with epirubicin (part 2). The primary endpoint was pCR (defined as absence of invasive cancer in the breast and axillary nodes, or ypT0/Tis ypN0) in the overall study population, and a pCR of 40% was considered a positive result.

A total of 29 patients were randomized to TP-A and 29 to TP alone in nine treatment centers in Austria. The study population ranged from 33 to 82 years, with a median age of 57 years. Most patients (72.4%) had hormone receptor (HR)–positive tumors; a total of 45 patients had stage IIA cancer, and 13 had stage IIB.

The primary endpoint of pCR occurred in 35 patients overall (60.3%). In a univariate analysis, the response rates were lower in HR-positive patients, in premenopausal patients, and in histologies other than NST (invasive carcinoma of no special type), Dr. Rinnerthaler said, but none of the differences were statistically significant, likely because of the small numbers in each group.

In an exploratory analysis of the ITT population with available PD-L1 data, the pCR was 69.2% for PD-L1–negative patients and 55.2% for PD-L1–positive patients.

“We observed the highest pCR rates in PD-L1–negative patients treated in the TP-A group and the lowest in PD-L1–positive patients treated with TP alone,” Dr. Rinnerthaler said.

No new safety concerns were observed during the study, Dr. Rinnerthaler noted. AEs of grade 3 or higher occurred in 17 patients (29.3%), including 9 in the TP-A group and 8 in the TP group. The most common AEs in both groups were nausea, diarrhea, and fatigue. No AEs of special interest of grade 3 or higher (defined as immune-related AEs, cardiac disorders, or infusion-related reactions) were observed.

The study findings were limited by the small sample size, but the resulting pCR rate of 60.3% was higher than the predefined threshold of 40% and supports additional research, said Dr. Rinnerthaler.

“For HER2-positive early breast cancer, a neoadjuvant chemotherapy de-escalation immunotherapy regimen with trastuzumab, pertuzumab, atezolizumab, and epirubicin is highly effective and safe and merits further investigation,” he concluded.

During a question-and-answer session, Dr. Rinnerthaler was asked why pCR increased in PD-L1 negative patients.

Previous data have shown that PD-L1 is up-regulated in certain tumors, and may serve as a surrogate for sensitivity, he said. In previous studies the additional effect of atezolizumab was seen in a PD-L1–negative group.

Dr. Rinnerthaler said he hopes to clarify this question when his research team reviews biopsy data from baseline and after the induction phase.
 

Defining response is key to de-escalation

In the IMpassion031 trial, “what we saw is a tendency to better outcomes for those patients who received atezolizumab,” said Matteo Lambertini, MD, of the University of Genova (Italy), who served as discussant for the two studies. The IMpassion031 study raises the question of where we are in the use of immuno-oncology for eTNBC. The study is now one of five neoadjuvant trials in this population.

Heidi Splete/MDedge News

Dr. Lambertini cited the KEYNOTE-522 study, which showed significant results in EFS. However, sample sizes and statistical design were different between these studies. “I think we need large studies of data in the adjuvant and postneoadjuvant setting for patients with triple-negative breast cancer.”

Postneoadjuvant considerations from the IMpassion031 trial showed good outcomes with no additional benefit of an immune checkpoint inhibitors.

For those patients with a pCR, it is definitely time to de-escalate treatment,” he said. In patients without pCR, escalation is needed, but an improved definition of pCR is also needed.

With regard to the ATHENE study, “it may be considered a positive study because the threshold of 40% was reached,” he said. The question is what is the optimum chemotherapy backbone. There appears to be no added benefit to adding an immune checkpoint inhibitor.

There are needs for defining the role of immunotherapy in HER2-positive breast cancer and more biomarker research to inform patient selection and study design, he said.

Finally, “I am not sure that the addition of an immune checkpoint inhibitor can be considered a de-escalation,” he noted.

IMpassion031 was supported by F. Hoffmann–La Roche. Dr. Barrio disclosed financial relationships with numerous companies. ABSCG-52/ATHENE was supported by the Austrian Breast and Colorectal Cancer Study Group and Roche Austria. Dr. Rinnerthaler disclosed relationships with multiple companies including Amgen, Daiichi Sankyo, Lilly, Gilead, MSD, Novartis, Pfizer, Roche, Seagen, and Pierre Fabre. Dr. Lambertini disclosed relationships with multiple companies including Roche, Novartis, AstraZeneca, Lilly, Exact Sciences, Pfizer, MSD, Seagen, Gilead, Takeda, Sandoz, Ipsen, Libbs, Knight, and Daiichi Sankyo.

Throughout the COVID-19 pandemic, health care professionals (HCPs), including emergency medicine physicians and hospitalists, have been continuously challenged to maintain an up-to-date clinical practice on COVID-19 therapeutics as new evidence emerged.^1,2 In the early part of the pandemic, these included not only appropriate and time-sensitive prescriptions of COVID-19 therapeutics, such as remdesivir and dexamethasone, but also judicious use of empiric antibiotics given the low prevalence for bacterial coinfection in early disease.^3-6 Alongside this, curbing the excessive laboratory testing of these patients during the pandemic was important not only to minimize costs but also to reduce potential iatrogenic harm and extended length of stay (LOS).⁷

At the beginning of the pandemic in March 2020 at the US Department of Veterans Affairs (VA) North Texas Health Care System (VANTHCS) Dallas VA Medical Center (DVAMC), we attempted to provide therapeutic guidance for physicians primarily through direct infectious disease (ID) consultation (in-person or electronic).⁸ This was secondarily supported by a pharmacist and ID physician–curated “living guidance” document on COVID-19 care accessible to all physicians through the DVAMC electronic health record (EHR) and intranet.

As the alpha variant (lineage B.1.1.7) of COVID-19 began spreading throughout North Texas in the winter of 2020, we implemented a targeted educational intervention toward the hospitalist group taking care of patients with COVID-19 with the primary goal of improving the accuracy of COVID-19 therapeutics while minimizing the consultative burden on ID clinical and pharmacy staff. This initiative consisted of (1) proactive guideline dissemination through email and text messages; (2) virtual didactics; and (3) physician reminders during the consultation process. Our ultimate aims were to improve hospitalist-led appropriate prescriptions of remdesivir and dexamethasone, reducing empiric antibiotic days of therapy in patients with COVID-19 at low risk of bacterial coinfection, and reducing laboratory orders that were not indicated for the management of these patients. Following this intervention and the resolution of the second wave, we retrospectively assessed the temporal trends of COVID-19 practices by hospitalists and associated patterns of ID consultation in the DVAMC from October 1, 2020, to March 31, 2021.

METHODS

The educational intervention was carried out at the DVAMC, a 1A high complex facility with more than 200 inpatient beds and part of the VANTHCS. During the study period, patients admitted with COVID-19 were located either on a closed floor (managed by the hospitalist team) or in a closed intensive care unit (ICU) (managed by the pulmonary/critical care team) contingent on the level of care or oxygen supplementation required. ID and other subspecialties provided consultation services as requested by hospitalists or ICU teams either electronically or in person. During the study period, 66 hospitalists were involved in the care of the patients: 59 (89.5%) permanent staff, 4 (6.0%) fee-basis physicians, and 3 (4.5%) moonlighting fellows.

Educational Initiative

We delivered educational sessions to the hospitalists, using collaboration software with video meeting capability every 1 to 2 months beginning in December 2020. An additional session focused on reducing empiric antibiotic prescriptions was also delivered to the emergency medicine department, based on feedback from the hospitalist group. The content for the educational sessions came from informal surveys of both ID trainees assigned to the consultation service and hospitalists, covering the following topics: understanding the stages of COVID-19 illness (virologic replication vs inflammatory) and rationales for therapy; assessing disease severity; indications and use of remdesivir; indications and use of dexamethasone; assessing for bacterial coinfections; when an ID consultation is required; management algorithm for COVID-19; and locating guidelines on the intranet. About 15 to 20 physicians participated in each session. In addition, slides of these didactics and updated institutional COVID-19 guidelines were disseminated to the hospitalist group via email and text messaging. We also linked the intranet institution guidelines in our communication, including a revised user-friendly flowchart (eAppendix).

Laboratory Stewardship Initiative

Laboratory stewardship initiatives were implemented by modifying suggested orders on the admission of patients with COVID-19 and directly educating hospitalist and emergency medicine physicians on evidence-based laboratory orders. At the beginning of the pandemic, a broad admission order set was established at DVAMC, based on the then limited knowledge of the course of infection with COVID-19. This order set allowed the admitting physicians to efficiently order laboratory tests for patients, especially during the demanding increase in patient volume experienced by DVAMC.

As new evidence emerged during the pandemic, many of the laboratory orders were reviewed for clinical utility during care for the patient with COVID-19 per the latest guidance. In December 2020, the admission orders for patients with COVID-19 were revised to reflect better laboratory stewardship to reduce cost and harm. The ID section revised the laboratory orders and disseminated the new order set to admitting physicians. Specifically, the admission order set removed the following laboratory tests available for selection: routine blood cultures, interleukin 6 (IL-6) level, and Legionella sputum culture. These laboratory orders were removed based on the lack of supporting evidence in persons admitted with COVID-19.⁹ In addition to modification of the admission order set, educational sessions were held with hospitalists to disseminate knowledge of the new changes and address any concerns.

Observations of Care

This study was approved by the VANTHCS Institutional Review Board (protocol code 20-047). Records were retrospectively reviewed for patients admitted to DVAMC for COVID-19 under hospitalist care (patients admitted directly to the ICU were excluded) from October 1, 2020, to March 31, 2021. Age, sex, race and ethnicity, and comorbidities were collected from the EHR. In addition clinical measures such as maximum oxygen requirement during admission (none, nasal cannula of 2-4 L/min, high flow/bilevel positive airway pressure [BiPAP] or mechanical ventilation), proven presence of coinfection (defined as the isolation of a probable pathogen in pure culture and/or clinically determined by ID specialist evaluation), and the average LOS also were collected. For laboratory stewardship data, a retrospective chart review was conducted to determine the total number of blood cultures obtained within 24 hours of admission per month during the study period. Both IL-6 levels and Legionella sputum culture data were collected as the total number of laboratory orders per month, as it was assumed that most of these orders were obtained for patients admitted with COVID-19.

Individual patient-level data were extracted to calculate monthly percentages of ID consultations for COVID-19 by the hospitalist team, adherence to institutional guidelines for dexamethasone and remdesivir prescriptions, and empiric antibiotic prescriptions for patients with COVID-19, including use of a priori adjudication criteria to determine justified vs unjustified empiric use. These criteria included asymmetric chest X-ray infiltrates concerning for bacterial pneumonia; peripheral white blood cell count > 11 K/μL; critical respiratory failure in the emergency department (ED) and being transferred to the ICU; and ID consultation recommended. Because the total number of antibiotics was not being analyzed but rather just the use of antibiotics for the justified and unjustified groups, antibiotic days were reported as the length of therapy (LOT).¹⁰ A subset analysis was performed on antibiotic prescriptions by the hospitalist group focusing on those with mild-to-moderate oxygen requirements (no high flow, noninvasive or invasive ventilatory methods) and excluding infections with a proven microbiologic entity.

Differences in demographic and clinical characteristics of patients with COVID-19 admitted from October 1, 2020, to March 31, 2021, were assessed using ANOVA, χ², and Kruskal-Wallis test. χ² was used to compare the difference in total laboratory orders for routine blood cultures, IL-6 levels, and Legionella sputum cultures between pre-intervention (October to December 2020) and postintervention (January to March 2021). These pre- and postintervention periods were determined based on the timing of revised admission orders in the EHR and initiation of focused educational sessions starting in late December 2020 and early January 2021. Linear regressions were used to examine the possible 6-month trend of the percentage of patients receiving ID consultation for appropriate dexamethasone prescriptions, appropriate remdesivir prescriptions, appropriate antibiotic coadministration, and mean number of antibiotic days per patient. Linear and logistic regression were also used to assess the trend in LOS over the 6 months while adjusting for age, race and ethnicity, sex, and coinfections. All analyses were performed using SAS 9.4. Statistical significance was defined as P < .05.

RESULTS

From October 1, 2020, to March 31, 2021, there were 565 admissions for COVID-19, which peaked in January 2021 with 163. Analysis of the patient characteristics showed no statistically significant difference for age, sex, oxygen requirements during admission, or proven presence of coinfection between the months of interest (Table 1).

The number of blood cultures obtained in the first 24 hours of admission significantly decreased from 58.1% of admissions in October 2020 to 34.8% of admissions in March 2021 (P < .01) (Table 2).

DISCUSSION

As the COVID-19 pandemic has evolved, the ability to enact up-to-date guidance is crucial to streamlining patient care, improving time to COVID-19–specific therapies, and minimizing the burden on subspecialty consultation services. At DVAMC, we initiated a targeted and deliberate educational effort directed toward hospitalist and ED groups combined with a laboratory stewardship effort over 6 months to improve the implementation of COVID-19 therapeutics, reduce empiric antibiotic use without reliance on ID consultation services, and reduce the number of unnecessary laboratory orders for admitted patients with COVID-19. During this time, we observed modest but statistically significant improvements in the accuracy of dexamethasone and remdesivir prescribing. In addition, we observed statistically significant improvement in the average LOT per patient regarding antibiotic use and overall decreased LOS. These improvements were seen in parallel with decreasing requests for ID consultation, suggesting that they were attributable in part to increasing self-confidence and efficacy in COVID-19 practices by the hospitalist group. Modification of the COVID-19 admission order set for our facility resulted in substantial decreases in orders for blood cultures, IL-6 levels, and sputum cultures for Legionella.

ID consultation, either in person or remotely, has been instrumental in assisting physicians in COVID-19 management and has been shown to reduce morbidity, mortality, and patient LOS in other infections.^11,12 However, in scenarios where ID consultation is not available or in limited supply, accessibility, familiarity, and confidence of primary practitioners to use therapeutic guidance material are integral. Frequent and accessible guidance for the management of COVID-19 has been provided by the National Institutes of Health and the Infectious Diseases Society of America.^13,14 Other mechanisms of assisting physicians in both test ordering and therapeutics include clinical decision support tools built into the EHR and the use of a smartphone digital application.¹⁵ Guidance needs to be adapted to the context of the facility, including available resources and specific restrictions and/or prohibitions on therapeutics (eg, mandatory ID consultation or approval). In our facility, while COVID-19 therapeutic living guidance documents were maintained and accessible through the intranet, proactive dissemination and redirection were important steps in enabling the use of these documents.

Limitations

We acknowledge several limitations to this study. Most important, the correlations we observed do not represent causation. Our analysis was not designed to ascertain the direct impact of any single or combined educational and laboratory stewardship intervention from this study, and we acknowledge that the improvements in part could be related to increased experience and confidence with COVID-19 management that occurred over time independent of our programs. Furthermore, we acknowledge that several areas of COVID-19 management did not improve over time (such as overall empiric antibiotic use from the ED) or had very modest improvements (hospitalist-initiated remdesivir use). These results underscore the complex dynamics and contextual barriers to rapidly implementing guideline-based care at VANTHCS. Potential factors include insufficient reach to all physicians, variable learner motivation, and therapeutic momentum of antibiotic use carried forward from the ED.^16,17 These factors should be considered as grounds for further study. Another limitation was the inability to track viewership and engagement of our COVID-19 guidance document. Without the use metrics, it is difficult to know the individual impact of the document regarding the changing trends in COVID-19 management we observed during the study period.

Conclusions

We report improvements in COVID-19 therapeutic prescriptions and the use of antibiotics and laboratory testing over 6 months at the DVAMC. This was correlated with a deliberate COVID-19 educational initiative that included antibiotic and laboratory stewardship interventions with simultaneous decreased reliance on ID consultation. These efforts lend support to the proof of the principle of combined educational and laboratory stewardship interventions to improve the care of COVID-19 patients, especially where ID support may not be available or is accessed remotely.

Throughout the COVID-19 pandemic, health care professionals (HCPs), including emergency medicine physicians and hospitalists, have been continuously challenged to maintain an up-to-date clinical practice on COVID-19 therapeutics as new evidence emerged.^1,2 In the early part of the pandemic, these included not only appropriate and time-sensitive prescriptions of COVID-19 therapeutics, such as remdesivir and dexamethasone, but also judicious use of empiric antibiotics given the low prevalence for bacterial coinfection in early disease.^3-6 Alongside this, curbing the excessive laboratory testing of these patients during the pandemic was important not only to minimize costs but also to reduce potential iatrogenic harm and extended length of stay (LOS).⁷

At the beginning of the pandemic in March 2020 at the US Department of Veterans Affairs (VA) North Texas Health Care System (VANTHCS) Dallas VA Medical Center (DVAMC), we attempted to provide therapeutic guidance for physicians primarily through direct infectious disease (ID) consultation (in-person or electronic).⁸ This was secondarily supported by a pharmacist and ID physician–curated “living guidance” document on COVID-19 care accessible to all physicians through the DVAMC electronic health record (EHR) and intranet.

As the alpha variant (lineage B.1.1.7) of COVID-19 began spreading throughout North Texas in the winter of 2020, we implemented a targeted educational intervention toward the hospitalist group taking care of patients with COVID-19 with the primary goal of improving the accuracy of COVID-19 therapeutics while minimizing the consultative burden on ID clinical and pharmacy staff. This initiative consisted of (1) proactive guideline dissemination through email and text messages; (2) virtual didactics; and (3) physician reminders during the consultation process. Our ultimate aims were to improve hospitalist-led appropriate prescriptions of remdesivir and dexamethasone, reducing empiric antibiotic days of therapy in patients with COVID-19 at low risk of bacterial coinfection, and reducing laboratory orders that were not indicated for the management of these patients. Following this intervention and the resolution of the second wave, we retrospectively assessed the temporal trends of COVID-19 practices by hospitalists and associated patterns of ID consultation in the DVAMC from October 1, 2020, to March 31, 2021.

METHODS

The educational intervention was carried out at the DVAMC, a 1A high complex facility with more than 200 inpatient beds and part of the VANTHCS. During the study period, patients admitted with COVID-19 were located either on a closed floor (managed by the hospitalist team) or in a closed intensive care unit (ICU) (managed by the pulmonary/critical care team) contingent on the level of care or oxygen supplementation required. ID and other subspecialties provided consultation services as requested by hospitalists or ICU teams either electronically or in person. During the study period, 66 hospitalists were involved in the care of the patients: 59 (89.5%) permanent staff, 4 (6.0%) fee-basis physicians, and 3 (4.5%) moonlighting fellows.

Educational Initiative

We delivered educational sessions to the hospitalists, using collaboration software with video meeting capability every 1 to 2 months beginning in December 2020. An additional session focused on reducing empiric antibiotic prescriptions was also delivered to the emergency medicine department, based on feedback from the hospitalist group. The content for the educational sessions came from informal surveys of both ID trainees assigned to the consultation service and hospitalists, covering the following topics: understanding the stages of COVID-19 illness (virologic replication vs inflammatory) and rationales for therapy; assessing disease severity; indications and use of remdesivir; indications and use of dexamethasone; assessing for bacterial coinfections; when an ID consultation is required; management algorithm for COVID-19; and locating guidelines on the intranet. About 15 to 20 physicians participated in each session. In addition, slides of these didactics and updated institutional COVID-19 guidelines were disseminated to the hospitalist group via email and text messaging. We also linked the intranet institution guidelines in our communication, including a revised user-friendly flowchart (eAppendix).

Laboratory Stewardship Initiative

Laboratory stewardship initiatives were implemented by modifying suggested orders on the admission of patients with COVID-19 and directly educating hospitalist and emergency medicine physicians on evidence-based laboratory orders. At the beginning of the pandemic, a broad admission order set was established at DVAMC, based on the then limited knowledge of the course of infection with COVID-19. This order set allowed the admitting physicians to efficiently order laboratory tests for patients, especially during the demanding increase in patient volume experienced by DVAMC.

As new evidence emerged during the pandemic, many of the laboratory orders were reviewed for clinical utility during care for the patient with COVID-19 per the latest guidance. In December 2020, the admission orders for patients with COVID-19 were revised to reflect better laboratory stewardship to reduce cost and harm. The ID section revised the laboratory orders and disseminated the new order set to admitting physicians. Specifically, the admission order set removed the following laboratory tests available for selection: routine blood cultures, interleukin 6 (IL-6) level, and Legionella sputum culture. These laboratory orders were removed based on the lack of supporting evidence in persons admitted with COVID-19.⁹ In addition to modification of the admission order set, educational sessions were held with hospitalists to disseminate knowledge of the new changes and address any concerns.

Observations of Care

This study was approved by the VANTHCS Institutional Review Board (protocol code 20-047). Records were retrospectively reviewed for patients admitted to DVAMC for COVID-19 under hospitalist care (patients admitted directly to the ICU were excluded) from October 1, 2020, to March 31, 2021. Age, sex, race and ethnicity, and comorbidities were collected from the EHR. In addition clinical measures such as maximum oxygen requirement during admission (none, nasal cannula of 2-4 L/min, high flow/bilevel positive airway pressure [BiPAP] or mechanical ventilation), proven presence of coinfection (defined as the isolation of a probable pathogen in pure culture and/or clinically determined by ID specialist evaluation), and the average LOS also were collected. For laboratory stewardship data, a retrospective chart review was conducted to determine the total number of blood cultures obtained within 24 hours of admission per month during the study period. Both IL-6 levels and Legionella sputum culture data were collected as the total number of laboratory orders per month, as it was assumed that most of these orders were obtained for patients admitted with COVID-19.

Individual patient-level data were extracted to calculate monthly percentages of ID consultations for COVID-19 by the hospitalist team, adherence to institutional guidelines for dexamethasone and remdesivir prescriptions, and empiric antibiotic prescriptions for patients with COVID-19, including use of a priori adjudication criteria to determine justified vs unjustified empiric use. These criteria included asymmetric chest X-ray infiltrates concerning for bacterial pneumonia; peripheral white blood cell count > 11 K/μL; critical respiratory failure in the emergency department (ED) and being transferred to the ICU; and ID consultation recommended. Because the total number of antibiotics was not being analyzed but rather just the use of antibiotics for the justified and unjustified groups, antibiotic days were reported as the length of therapy (LOT).¹⁰ A subset analysis was performed on antibiotic prescriptions by the hospitalist group focusing on those with mild-to-moderate oxygen requirements (no high flow, noninvasive or invasive ventilatory methods) and excluding infections with a proven microbiologic entity.

Differences in demographic and clinical characteristics of patients with COVID-19 admitted from October 1, 2020, to March 31, 2021, were assessed using ANOVA, χ², and Kruskal-Wallis test. χ² was used to compare the difference in total laboratory orders for routine blood cultures, IL-6 levels, and Legionella sputum cultures between pre-intervention (October to December 2020) and postintervention (January to March 2021). These pre- and postintervention periods were determined based on the timing of revised admission orders in the EHR and initiation of focused educational sessions starting in late December 2020 and early January 2021. Linear regressions were used to examine the possible 6-month trend of the percentage of patients receiving ID consultation for appropriate dexamethasone prescriptions, appropriate remdesivir prescriptions, appropriate antibiotic coadministration, and mean number of antibiotic days per patient. Linear and logistic regression were also used to assess the trend in LOS over the 6 months while adjusting for age, race and ethnicity, sex, and coinfections. All analyses were performed using SAS 9.4. Statistical significance was defined as P < .05.

RESULTS

From October 1, 2020, to March 31, 2021, there were 565 admissions for COVID-19, which peaked in January 2021 with 163. Analysis of the patient characteristics showed no statistically significant difference for age, sex, oxygen requirements during admission, or proven presence of coinfection between the months of interest (Table 1).

The number of blood cultures obtained in the first 24 hours of admission significantly decreased from 58.1% of admissions in October 2020 to 34.8% of admissions in March 2021 (P < .01) (Table 2).

DISCUSSION

As the COVID-19 pandemic has evolved, the ability to enact up-to-date guidance is crucial to streamlining patient care, improving time to COVID-19–specific therapies, and minimizing the burden on subspecialty consultation services. At DVAMC, we initiated a targeted and deliberate educational effort directed toward hospitalist and ED groups combined with a laboratory stewardship effort over 6 months to improve the implementation of COVID-19 therapeutics, reduce empiric antibiotic use without reliance on ID consultation services, and reduce the number of unnecessary laboratory orders for admitted patients with COVID-19. During this time, we observed modest but statistically significant improvements in the accuracy of dexamethasone and remdesivir prescribing. In addition, we observed statistically significant improvement in the average LOT per patient regarding antibiotic use and overall decreased LOS. These improvements were seen in parallel with decreasing requests for ID consultation, suggesting that they were attributable in part to increasing self-confidence and efficacy in COVID-19 practices by the hospitalist group. Modification of the COVID-19 admission order set for our facility resulted in substantial decreases in orders for blood cultures, IL-6 levels, and sputum cultures for Legionella.

ID consultation, either in person or remotely, has been instrumental in assisting physicians in COVID-19 management and has been shown to reduce morbidity, mortality, and patient LOS in other infections.^11,12 However, in scenarios where ID consultation is not available or in limited supply, accessibility, familiarity, and confidence of primary practitioners to use therapeutic guidance material are integral. Frequent and accessible guidance for the management of COVID-19 has been provided by the National Institutes of Health and the Infectious Diseases Society of America.^13,14 Other mechanisms of assisting physicians in both test ordering and therapeutics include clinical decision support tools built into the EHR and the use of a smartphone digital application.¹⁵ Guidance needs to be adapted to the context of the facility, including available resources and specific restrictions and/or prohibitions on therapeutics (eg, mandatory ID consultation or approval). In our facility, while COVID-19 therapeutic living guidance documents were maintained and accessible through the intranet, proactive dissemination and redirection were important steps in enabling the use of these documents.

Limitations

We acknowledge several limitations to this study. Most important, the correlations we observed do not represent causation. Our analysis was not designed to ascertain the direct impact of any single or combined educational and laboratory stewardship intervention from this study, and we acknowledge that the improvements in part could be related to increased experience and confidence with COVID-19 management that occurred over time independent of our programs. Furthermore, we acknowledge that several areas of COVID-19 management did not improve over time (such as overall empiric antibiotic use from the ED) or had very modest improvements (hospitalist-initiated remdesivir use). These results underscore the complex dynamics and contextual barriers to rapidly implementing guideline-based care at VANTHCS. Potential factors include insufficient reach to all physicians, variable learner motivation, and therapeutic momentum of antibiotic use carried forward from the ED.^16,17 These factors should be considered as grounds for further study. Another limitation was the inability to track viewership and engagement of our COVID-19 guidance document. Without the use metrics, it is difficult to know the individual impact of the document regarding the changing trends in COVID-19 management we observed during the study period.

Conclusions

We report improvements in COVID-19 therapeutic prescriptions and the use of antibiotics and laboratory testing over 6 months at the DVAMC. This was correlated with a deliberate COVID-19 educational initiative that included antibiotic and laboratory stewardship interventions with simultaneous decreased reliance on ID consultation. These efforts lend support to the proof of the principle of combined educational and laboratory stewardship interventions to improve the care of COVID-19 patients, especially where ID support may not be available or is accessed remotely.

Throughout the COVID-19 pandemic, health care professionals (HCPs), including emergency medicine physicians and hospitalists, have been continuously challenged to maintain an up-to-date clinical practice on COVID-19 therapeutics as new evidence emerged.^1,2 In the early part of the pandemic, these included not only appropriate and time-sensitive prescriptions of COVID-19 therapeutics, such as remdesivir and dexamethasone, but also judicious use of empiric antibiotics given the low prevalence for bacterial coinfection in early disease.^3-6 Alongside this, curbing the excessive laboratory testing of these patients during the pandemic was important not only to minimize costs but also to reduce potential iatrogenic harm and extended length of stay (LOS).⁷

At the beginning of the pandemic in March 2020 at the US Department of Veterans Affairs (VA) North Texas Health Care System (VANTHCS) Dallas VA Medical Center (DVAMC), we attempted to provide therapeutic guidance for physicians primarily through direct infectious disease (ID) consultation (in-person or electronic).⁸ This was secondarily supported by a pharmacist and ID physician–curated “living guidance” document on COVID-19 care accessible to all physicians through the DVAMC electronic health record (EHR) and intranet.

As the alpha variant (lineage B.1.1.7) of COVID-19 began spreading throughout North Texas in the winter of 2020, we implemented a targeted educational intervention toward the hospitalist group taking care of patients with COVID-19 with the primary goal of improving the accuracy of COVID-19 therapeutics while minimizing the consultative burden on ID clinical and pharmacy staff. This initiative consisted of (1) proactive guideline dissemination through email and text messages; (2) virtual didactics; and (3) physician reminders during the consultation process. Our ultimate aims were to improve hospitalist-led appropriate prescriptions of remdesivir and dexamethasone, reducing empiric antibiotic days of therapy in patients with COVID-19 at low risk of bacterial coinfection, and reducing laboratory orders that were not indicated for the management of these patients. Following this intervention and the resolution of the second wave, we retrospectively assessed the temporal trends of COVID-19 practices by hospitalists and associated patterns of ID consultation in the DVAMC from October 1, 2020, to March 31, 2021.

METHODS

The educational intervention was carried out at the DVAMC, a 1A high complex facility with more than 200 inpatient beds and part of the VANTHCS. During the study period, patients admitted with COVID-19 were located either on a closed floor (managed by the hospitalist team) or in a closed intensive care unit (ICU) (managed by the pulmonary/critical care team) contingent on the level of care or oxygen supplementation required. ID and other subspecialties provided consultation services as requested by hospitalists or ICU teams either electronically or in person. During the study period, 66 hospitalists were involved in the care of the patients: 59 (89.5%) permanent staff, 4 (6.0%) fee-basis physicians, and 3 (4.5%) moonlighting fellows.

Educational Initiative

We delivered educational sessions to the hospitalists, using collaboration software with video meeting capability every 1 to 2 months beginning in December 2020. An additional session focused on reducing empiric antibiotic prescriptions was also delivered to the emergency medicine department, based on feedback from the hospitalist group. The content for the educational sessions came from informal surveys of both ID trainees assigned to the consultation service and hospitalists, covering the following topics: understanding the stages of COVID-19 illness (virologic replication vs inflammatory) and rationales for therapy; assessing disease severity; indications and use of remdesivir; indications and use of dexamethasone; assessing for bacterial coinfections; when an ID consultation is required; management algorithm for COVID-19; and locating guidelines on the intranet. About 15 to 20 physicians participated in each session. In addition, slides of these didactics and updated institutional COVID-19 guidelines were disseminated to the hospitalist group via email and text messaging. We also linked the intranet institution guidelines in our communication, including a revised user-friendly flowchart (eAppendix).

Laboratory Stewardship Initiative

Laboratory stewardship initiatives were implemented by modifying suggested orders on the admission of patients with COVID-19 and directly educating hospitalist and emergency medicine physicians on evidence-based laboratory orders. At the beginning of the pandemic, a broad admission order set was established at DVAMC, based on the then limited knowledge of the course of infection with COVID-19. This order set allowed the admitting physicians to efficiently order laboratory tests for patients, especially during the demanding increase in patient volume experienced by DVAMC.

As new evidence emerged during the pandemic, many of the laboratory orders were reviewed for clinical utility during care for the patient with COVID-19 per the latest guidance. In December 2020, the admission orders for patients with COVID-19 were revised to reflect better laboratory stewardship to reduce cost and harm. The ID section revised the laboratory orders and disseminated the new order set to admitting physicians. Specifically, the admission order set removed the following laboratory tests available for selection: routine blood cultures, interleukin 6 (IL-6) level, and Legionella sputum culture. These laboratory orders were removed based on the lack of supporting evidence in persons admitted with COVID-19.⁹ In addition to modification of the admission order set, educational sessions were held with hospitalists to disseminate knowledge of the new changes and address any concerns.

Observations of Care

This study was approved by the VANTHCS Institutional Review Board (protocol code 20-047). Records were retrospectively reviewed for patients admitted to DVAMC for COVID-19 under hospitalist care (patients admitted directly to the ICU were excluded) from October 1, 2020, to March 31, 2021. Age, sex, race and ethnicity, and comorbidities were collected from the EHR. In addition clinical measures such as maximum oxygen requirement during admission (none, nasal cannula of 2-4 L/min, high flow/bilevel positive airway pressure [BiPAP] or mechanical ventilation), proven presence of coinfection (defined as the isolation of a probable pathogen in pure culture and/or clinically determined by ID specialist evaluation), and the average LOS also were collected. For laboratory stewardship data, a retrospective chart review was conducted to determine the total number of blood cultures obtained within 24 hours of admission per month during the study period. Both IL-6 levels and Legionella sputum culture data were collected as the total number of laboratory orders per month, as it was assumed that most of these orders were obtained for patients admitted with COVID-19.

Individual patient-level data were extracted to calculate monthly percentages of ID consultations for COVID-19 by the hospitalist team, adherence to institutional guidelines for dexamethasone and remdesivir prescriptions, and empiric antibiotic prescriptions for patients with COVID-19, including use of a priori adjudication criteria to determine justified vs unjustified empiric use. These criteria included asymmetric chest X-ray infiltrates concerning for bacterial pneumonia; peripheral white blood cell count > 11 K/μL; critical respiratory failure in the emergency department (ED) and being transferred to the ICU; and ID consultation recommended. Because the total number of antibiotics was not being analyzed but rather just the use of antibiotics for the justified and unjustified groups, antibiotic days were reported as the length of therapy (LOT).¹⁰ A subset analysis was performed on antibiotic prescriptions by the hospitalist group focusing on those with mild-to-moderate oxygen requirements (no high flow, noninvasive or invasive ventilatory methods) and excluding infections with a proven microbiologic entity.

Differences in demographic and clinical characteristics of patients with COVID-19 admitted from October 1, 2020, to March 31, 2021, were assessed using ANOVA, χ², and Kruskal-Wallis test. χ² was used to compare the difference in total laboratory orders for routine blood cultures, IL-6 levels, and Legionella sputum cultures between pre-intervention (October to December 2020) and postintervention (January to March 2021). These pre- and postintervention periods were determined based on the timing of revised admission orders in the EHR and initiation of focused educational sessions starting in late December 2020 and early January 2021. Linear regressions were used to examine the possible 6-month trend of the percentage of patients receiving ID consultation for appropriate dexamethasone prescriptions, appropriate remdesivir prescriptions, appropriate antibiotic coadministration, and mean number of antibiotic days per patient. Linear and logistic regression were also used to assess the trend in LOS over the 6 months while adjusting for age, race and ethnicity, sex, and coinfections. All analyses were performed using SAS 9.4. Statistical significance was defined as P < .05.

RESULTS

From October 1, 2020, to March 31, 2021, there were 565 admissions for COVID-19, which peaked in January 2021 with 163. Analysis of the patient characteristics showed no statistically significant difference for age, sex, oxygen requirements during admission, or proven presence of coinfection between the months of interest (Table 1).

The number of blood cultures obtained in the first 24 hours of admission significantly decreased from 58.1% of admissions in October 2020 to 34.8% of admissions in March 2021 (P < .01) (Table 2).

DISCUSSION

As the COVID-19 pandemic has evolved, the ability to enact up-to-date guidance is crucial to streamlining patient care, improving time to COVID-19–specific therapies, and minimizing the burden on subspecialty consultation services. At DVAMC, we initiated a targeted and deliberate educational effort directed toward hospitalist and ED groups combined with a laboratory stewardship effort over 6 months to improve the implementation of COVID-19 therapeutics, reduce empiric antibiotic use without reliance on ID consultation services, and reduce the number of unnecessary laboratory orders for admitted patients with COVID-19. During this time, we observed modest but statistically significant improvements in the accuracy of dexamethasone and remdesivir prescribing. In addition, we observed statistically significant improvement in the average LOT per patient regarding antibiotic use and overall decreased LOS. These improvements were seen in parallel with decreasing requests for ID consultation, suggesting that they were attributable in part to increasing self-confidence and efficacy in COVID-19 practices by the hospitalist group. Modification of the COVID-19 admission order set for our facility resulted in substantial decreases in orders for blood cultures, IL-6 levels, and sputum cultures for Legionella.

ID consultation, either in person or remotely, has been instrumental in assisting physicians in COVID-19 management and has been shown to reduce morbidity, mortality, and patient LOS in other infections.^11,12 However, in scenarios where ID consultation is not available or in limited supply, accessibility, familiarity, and confidence of primary practitioners to use therapeutic guidance material are integral. Frequent and accessible guidance for the management of COVID-19 has been provided by the National Institutes of Health and the Infectious Diseases Society of America.^13,14 Other mechanisms of assisting physicians in both test ordering and therapeutics include clinical decision support tools built into the EHR and the use of a smartphone digital application.¹⁵ Guidance needs to be adapted to the context of the facility, including available resources and specific restrictions and/or prohibitions on therapeutics (eg, mandatory ID consultation or approval). In our facility, while COVID-19 therapeutic living guidance documents were maintained and accessible through the intranet, proactive dissemination and redirection were important steps in enabling the use of these documents.

Limitations

We acknowledge several limitations to this study. Most important, the correlations we observed do not represent causation. Our analysis was not designed to ascertain the direct impact of any single or combined educational and laboratory stewardship intervention from this study, and we acknowledge that the improvements in part could be related to increased experience and confidence with COVID-19 management that occurred over time independent of our programs. Furthermore, we acknowledge that several areas of COVID-19 management did not improve over time (such as overall empiric antibiotic use from the ED) or had very modest improvements (hospitalist-initiated remdesivir use). These results underscore the complex dynamics and contextual barriers to rapidly implementing guideline-based care at VANTHCS. Potential factors include insufficient reach to all physicians, variable learner motivation, and therapeutic momentum of antibiotic use carried forward from the ED.^16,17 These factors should be considered as grounds for further study. Another limitation was the inability to track viewership and engagement of our COVID-19 guidance document. Without the use metrics, it is difficult to know the individual impact of the document regarding the changing trends in COVID-19 management we observed during the study period.

Conclusions

We report improvements in COVID-19 therapeutic prescriptions and the use of antibiotics and laboratory testing over 6 months at the DVAMC. This was correlated with a deliberate COVID-19 educational initiative that included antibiotic and laboratory stewardship interventions with simultaneous decreased reliance on ID consultation. These efforts lend support to the proof of the principle of combined educational and laboratory stewardship interventions to improve the care of COVID-19 patients, especially where ID support may not be available or is accessed remotely.

BY ALICIA AULT

The Centers for Disease Control and Prevention is alerting clinicians to be on the lookout for a severe antifungal-resistant form of tinea, as it was recently detected in two patients in New York.

Tinea, or ringworm, one of the most common fungal infections, is responsible for almost 5 million outpatient visits and 690 hospitalizations annually, according to the CDC.

Over the past 10 years, severe, antifungal-resistant tinea has spread in South Asia, in part because of the rise of a new dermatophyte species known as Trichophyton indotineae, wrote the authors of a report on the two patients with the drug-resistant strain. This epidemic “has likely been driven by misuse and overuse of topical antifungals and corticosteroids,” added the authors, in Morbidity and Mortality Weekly Report.

The cases were detected by a New York City dermatologist. In the first case, a 28-year-old woman developed a widespread pruritic eruption in the summer of 2021. She did not consult a dermatologist until December, when she was in the third trimester of pregnancy. She had large, annular, scaly, pruritic plaques on her neck, abdomen, pubic region, and buttocks, but had no underlying medical conditions, no known exposures to someone with a similar rash, and no recent international travel history.

After she gave birth in January, she started oral terbinafine therapy but had no improvement after 2 weeks. Clinicians administered a 4-week course of itraconazole, which resolved the infection.

The second patient, a 47-year-old woman with no medical conditions, developed a rash while in Bangladesh in the summer of 2022. Other family members had a similar rash. She was treated with topical antifungal and steroid combination creams but had no resolution. Back in the United States, she was prescribed hydrocortisone 2.5% ointment and diphenhydramine, clotrimazole cream, and terbinafine cream in three successive emergency department visits. In December 2022, dermatologists, observing widespread, discrete, scaly, annular, pruritic plaques on the thighs and buttocks, prescribed a 4-week course of oral terbinafine. When the rash did not resolve, she was given 4 weeks of griseofulvin. The rash persisted, although there was 80% improvement. Clinicians are now considering itraconazole. The woman’s son and husband are also being evaluated, as they have similar rashes.

In both cases, skin culture isolates were initially identified as Trichophyton mentagrophytes. Further analysis at the New York State Department of Health’s lab, using Sanger sequencing of the internal transcribed spacer region of the ribosomal gene, followed by phylogenetic analysis, identified the isolates as T. indotineae.

The authors note that culture-based techniques used by most clinical laboratories typically misidentify T. indotineae as T. mentagrophytes or T. interdigitale. Genomic sequencing must be used to properly identify T. indotineae, they wrote.

Clinicians should consider T. indotineae in patients with widespread ringworm, especially if they do not improve with topical antifungals or oral terbinafine, said the authors. If T. indotineae is suspected, state or local public health departments can direct clinicians to testing.

The authors report no relevant financial relationships.

BY ALICIA AULT

The Centers for Disease Control and Prevention is alerting clinicians to be on the lookout for a severe antifungal-resistant form of tinea, as it was recently detected in two patients in New York.

Tinea, or ringworm, one of the most common fungal infections, is responsible for almost 5 million outpatient visits and 690 hospitalizations annually, according to the CDC.

Over the past 10 years, severe, antifungal-resistant tinea has spread in South Asia, in part because of the rise of a new dermatophyte species known as Trichophyton indotineae, wrote the authors of a report on the two patients with the drug-resistant strain. This epidemic “has likely been driven by misuse and overuse of topical antifungals and corticosteroids,” added the authors, in Morbidity and Mortality Weekly Report.

The cases were detected by a New York City dermatologist. In the first case, a 28-year-old woman developed a widespread pruritic eruption in the summer of 2021. She did not consult a dermatologist until December, when she was in the third trimester of pregnancy. She had large, annular, scaly, pruritic plaques on her neck, abdomen, pubic region, and buttocks, but had no underlying medical conditions, no known exposures to someone with a similar rash, and no recent international travel history.

After she gave birth in January, she started oral terbinafine therapy but had no improvement after 2 weeks. Clinicians administered a 4-week course of itraconazole, which resolved the infection.

The second patient, a 47-year-old woman with no medical conditions, developed a rash while in Bangladesh in the summer of 2022. Other family members had a similar rash. She was treated with topical antifungal and steroid combination creams but had no resolution. Back in the United States, she was prescribed hydrocortisone 2.5% ointment and diphenhydramine, clotrimazole cream, and terbinafine cream in three successive emergency department visits. In December 2022, dermatologists, observing widespread, discrete, scaly, annular, pruritic plaques on the thighs and buttocks, prescribed a 4-week course of oral terbinafine. When the rash did not resolve, she was given 4 weeks of griseofulvin. The rash persisted, although there was 80% improvement. Clinicians are now considering itraconazole. The woman’s son and husband are also being evaluated, as they have similar rashes.

In both cases, skin culture isolates were initially identified as Trichophyton mentagrophytes. Further analysis at the New York State Department of Health’s lab, using Sanger sequencing of the internal transcribed spacer region of the ribosomal gene, followed by phylogenetic analysis, identified the isolates as T. indotineae.

The authors note that culture-based techniques used by most clinical laboratories typically misidentify T. indotineae as T. mentagrophytes or T. interdigitale. Genomic sequencing must be used to properly identify T. indotineae, they wrote.

Clinicians should consider T. indotineae in patients with widespread ringworm, especially if they do not improve with topical antifungals or oral terbinafine, said the authors. If T. indotineae is suspected, state or local public health departments can direct clinicians to testing.

The authors report no relevant financial relationships.

BY ALICIA AULT

The Centers for Disease Control and Prevention is alerting clinicians to be on the lookout for a severe antifungal-resistant form of tinea, as it was recently detected in two patients in New York.

Tinea, or ringworm, one of the most common fungal infections, is responsible for almost 5 million outpatient visits and 690 hospitalizations annually, according to the CDC.

Over the past 10 years, severe, antifungal-resistant tinea has spread in South Asia, in part because of the rise of a new dermatophyte species known as Trichophyton indotineae, wrote the authors of a report on the two patients with the drug-resistant strain. This epidemic “has likely been driven by misuse and overuse of topical antifungals and corticosteroids,” added the authors, in Morbidity and Mortality Weekly Report.

The cases were detected by a New York City dermatologist. In the first case, a 28-year-old woman developed a widespread pruritic eruption in the summer of 2021. She did not consult a dermatologist until December, when she was in the third trimester of pregnancy. She had large, annular, scaly, pruritic plaques on her neck, abdomen, pubic region, and buttocks, but had no underlying medical conditions, no known exposures to someone with a similar rash, and no recent international travel history.

After she gave birth in January, she started oral terbinafine therapy but had no improvement after 2 weeks. Clinicians administered a 4-week course of itraconazole, which resolved the infection.

The second patient, a 47-year-old woman with no medical conditions, developed a rash while in Bangladesh in the summer of 2022. Other family members had a similar rash. She was treated with topical antifungal and steroid combination creams but had no resolution. Back in the United States, she was prescribed hydrocortisone 2.5% ointment and diphenhydramine, clotrimazole cream, and terbinafine cream in three successive emergency department visits. In December 2022, dermatologists, observing widespread, discrete, scaly, annular, pruritic plaques on the thighs and buttocks, prescribed a 4-week course of oral terbinafine. When the rash did not resolve, she was given 4 weeks of griseofulvin. The rash persisted, although there was 80% improvement. Clinicians are now considering itraconazole. The woman’s son and husband are also being evaluated, as they have similar rashes.

In both cases, skin culture isolates were initially identified as Trichophyton mentagrophytes. Further analysis at the New York State Department of Health’s lab, using Sanger sequencing of the internal transcribed spacer region of the ribosomal gene, followed by phylogenetic analysis, identified the isolates as T. indotineae.

The authors note that culture-based techniques used by most clinical laboratories typically misidentify T. indotineae as T. mentagrophytes or T. interdigitale. Genomic sequencing must be used to properly identify T. indotineae, they wrote.

Clinicians should consider T. indotineae in patients with widespread ringworm, especially if they do not improve with topical antifungals or oral terbinafine, said the authors. If T. indotineae is suspected, state or local public health departments can direct clinicians to testing.

The authors report no relevant financial relationships.

It has been a troubling mystery—and yet, is an unsolved one: Last January, at least 9 service members who had worked at Malmstrom Air Force Base (AFB) in Montana were reported to have been diagnosed with non-Hodgkin lymphoma. Then more cancer cases were reported, not only at Malmstrom, but at Francis E. Warren AFB in Wyoming, Minot AFB in North Dakota, and Vandenberg AFB in California. The bases operate the silos that house nuclear warheads carried by Minuteman III intercontinental ballistic missiles (ICBMs).

In all, 36 cancer cases were reported among missileers: 10 developed non-Hodgkin lymphoma, 2 Hodgkin lymphoma, and 24 another form of cancer. Eight of the missileers, the majority of whom served at Malmstrom between 1997 and 2007, have died.

So far, though, the US Air Force (USAF) reports that it has found no current risk factors that could explain the unusual number of cases.

In February, Gen. Thomas Bussiere, commander of Air Force Global Strike Command, approved a study to conduct a formal assessment related to specific cancer concerns and examine the possibility of cancer clusters at ICBM bases. The Missile Community Cancer Study, conducted by the Air Force School of Aerospace Medicine, will look at all ICBM wings, all missileers, and those who maintain, guard, and support the bases. The review also incorporates active-duty medical data, the US Department of Veterans Affairs cancer registry data, mortality data, and public cancer registries.

Missileers may be exposed to a variety of chemicals and toxins. The potential hazardous materials exposure at the missile silos extends to all 3 missile bases, USAF says. The equipment in the launch control center and equipment buildings were identical. However, each of the ICBM bases has specific environmental and agricultural factors that will be considered as studies continue, according to the USAF. The land surrounding missile alert facilities, launch control centers, and launch facilities is not owned by the government; the study teams noted that locations could contain additional unknown agricultural hazards. Procedures for testing and cleaning the facilities vary across installations, creating inconsistencies, according to the USAF.

The study teams recently presented their initial findings. “[O]verall,” they said, “there were no factors identified that would be considered immediate concerns for acute cancer risks,” according to a report from the USAF 711^th Human Performance Wing, obtained by the Associated Press.

This isn’t the first time that concerns have been raised about possible cancer clusters at Malmstrom. In 2001, after cases of various cancers from missileers were reported—including cervical, thyroid, Hodgkin lymphoma, and non-Hodgkin lymphoma—the Air Force Institute for Operational Health conducted a site evaluation and sampling for possible chemical and biologic contaminants at their facilities. Results of all tests, the 2005 report said, did not demonstrate any levels above acceptable standards according to state and federal regulations. The survey concluded that launch control centers provide a safe and healthy working environment.

In 2005, following the release of the report, the USAF said “There is not sufficient evidence to consider the possibility of a cancer clustering to justify further investigation.” The research report noted, “[S]ometimes illnesses tend to occur by chance alone and it is not uncommon to see clustering or what has been referred to as ‘perceived clustering’ of conditions, especially when they occur in a close group of people or certain communities as in the military.”

On its website, though, the Air Force Medical Service now says that the findings from 2 decades ago may have changed.

The findings from the new study are not final. The USAF is continuing its investigation, including conducting an epidemiological study of cancers within the missile community. In the meantime, Air Force Global Strike Command Public Affairs says that, in response to the review panel’s recommendations, Gen. Bussiere has directed that facilities be deep cleaned regularly, signage denoting the presence of polychlorinated biphenyls be updated, and burning no longer allowed as a means of destroying classified materials inside the facilities.

Notably, the changes will also include improving communication and coordination between medical personnel and missile community members. Bussiere directed his staff to explore specifically assigning medical professionals to ICBM units, to have a better understanding of the environment and missions. He also ordered further engagement with personnel who work with known occupational hazards to collect more data and information. While awaiting the eventual replacement of the Minuteman III ICBM with the LGM-35A Sentinel, preventive maintenance and environmental upgrades will be prioritized and any upgrade or new piece of equipment will be “scrutinized for hazards.”

The USAF has also established a website to address the missileer community’s concerns.

It has been a troubling mystery—and yet, is an unsolved one: Last January, at least 9 service members who had worked at Malmstrom Air Force Base (AFB) in Montana were reported to have been diagnosed with non-Hodgkin lymphoma. Then more cancer cases were reported, not only at Malmstrom, but at Francis E. Warren AFB in Wyoming, Minot AFB in North Dakota, and Vandenberg AFB in California. The bases operate the silos that house nuclear warheads carried by Minuteman III intercontinental ballistic missiles (ICBMs).

In all, 36 cancer cases were reported among missileers: 10 developed non-Hodgkin lymphoma, 2 Hodgkin lymphoma, and 24 another form of cancer. Eight of the missileers, the majority of whom served at Malmstrom between 1997 and 2007, have died.

So far, though, the US Air Force (USAF) reports that it has found no current risk factors that could explain the unusual number of cases.

In February, Gen. Thomas Bussiere, commander of Air Force Global Strike Command, approved a study to conduct a formal assessment related to specific cancer concerns and examine the possibility of cancer clusters at ICBM bases. The Missile Community Cancer Study, conducted by the Air Force School of Aerospace Medicine, will look at all ICBM wings, all missileers, and those who maintain, guard, and support the bases. The review also incorporates active-duty medical data, the US Department of Veterans Affairs cancer registry data, mortality data, and public cancer registries.

Missileers may be exposed to a variety of chemicals and toxins. The potential hazardous materials exposure at the missile silos extends to all 3 missile bases, USAF says. The equipment in the launch control center and equipment buildings were identical. However, each of the ICBM bases has specific environmental and agricultural factors that will be considered as studies continue, according to the USAF. The land surrounding missile alert facilities, launch control centers, and launch facilities is not owned by the government; the study teams noted that locations could contain additional unknown agricultural hazards. Procedures for testing and cleaning the facilities vary across installations, creating inconsistencies, according to the USAF.

The study teams recently presented their initial findings. “[O]verall,” they said, “there were no factors identified that would be considered immediate concerns for acute cancer risks,” according to a report from the USAF 711^th Human Performance Wing, obtained by the Associated Press.

This isn’t the first time that concerns have been raised about possible cancer clusters at Malmstrom. In 2001, after cases of various cancers from missileers were reported—including cervical, thyroid, Hodgkin lymphoma, and non-Hodgkin lymphoma—the Air Force Institute for Operational Health conducted a site evaluation and sampling for possible chemical and biologic contaminants at their facilities. Results of all tests, the 2005 report said, did not demonstrate any levels above acceptable standards according to state and federal regulations. The survey concluded that launch control centers provide a safe and healthy working environment.

In 2005, following the release of the report, the USAF said “There is not sufficient evidence to consider the possibility of a cancer clustering to justify further investigation.” The research report noted, “[S]ometimes illnesses tend to occur by chance alone and it is not uncommon to see clustering or what has been referred to as ‘perceived clustering’ of conditions, especially when they occur in a close group of people or certain communities as in the military.”

On its website, though, the Air Force Medical Service now says that the findings from 2 decades ago may have changed.

The findings from the new study are not final. The USAF is continuing its investigation, including conducting an epidemiological study of cancers within the missile community. In the meantime, Air Force Global Strike Command Public Affairs says that, in response to the review panel’s recommendations, Gen. Bussiere has directed that facilities be deep cleaned regularly, signage denoting the presence of polychlorinated biphenyls be updated, and burning no longer allowed as a means of destroying classified materials inside the facilities.

Notably, the changes will also include improving communication and coordination between medical personnel and missile community members. Bussiere directed his staff to explore specifically assigning medical professionals to ICBM units, to have a better understanding of the environment and missions. He also ordered further engagement with personnel who work with known occupational hazards to collect more data and information. While awaiting the eventual replacement of the Minuteman III ICBM with the LGM-35A Sentinel, preventive maintenance and environmental upgrades will be prioritized and any upgrade or new piece of equipment will be “scrutinized for hazards.”

The USAF has also established a website to address the missileer community’s concerns.

It has been a troubling mystery—and yet, is an unsolved one: Last January, at least 9 service members who had worked at Malmstrom Air Force Base (AFB) in Montana were reported to have been diagnosed with non-Hodgkin lymphoma. Then more cancer cases were reported, not only at Malmstrom, but at Francis E. Warren AFB in Wyoming, Minot AFB in North Dakota, and Vandenberg AFB in California. The bases operate the silos that house nuclear warheads carried by Minuteman III intercontinental ballistic missiles (ICBMs).

In all, 36 cancer cases were reported among missileers: 10 developed non-Hodgkin lymphoma, 2 Hodgkin lymphoma, and 24 another form of cancer. Eight of the missileers, the majority of whom served at Malmstrom between 1997 and 2007, have died.

So far, though, the US Air Force (USAF) reports that it has found no current risk factors that could explain the unusual number of cases.

In February, Gen. Thomas Bussiere, commander of Air Force Global Strike Command, approved a study to conduct a formal assessment related to specific cancer concerns and examine the possibility of cancer clusters at ICBM bases. The Missile Community Cancer Study, conducted by the Air Force School of Aerospace Medicine, will look at all ICBM wings, all missileers, and those who maintain, guard, and support the bases. The review also incorporates active-duty medical data, the US Department of Veterans Affairs cancer registry data, mortality data, and public cancer registries.

Missileers may be exposed to a variety of chemicals and toxins. The potential hazardous materials exposure at the missile silos extends to all 3 missile bases, USAF says. The equipment in the launch control center and equipment buildings were identical. However, each of the ICBM bases has specific environmental and agricultural factors that will be considered as studies continue, according to the USAF. The land surrounding missile alert facilities, launch control centers, and launch facilities is not owned by the government; the study teams noted that locations could contain additional unknown agricultural hazards. Procedures for testing and cleaning the facilities vary across installations, creating inconsistencies, according to the USAF.

The study teams recently presented their initial findings. “[O]verall,” they said, “there were no factors identified that would be considered immediate concerns for acute cancer risks,” according to a report from the USAF 711^th Human Performance Wing, obtained by the Associated Press.

This isn’t the first time that concerns have been raised about possible cancer clusters at Malmstrom. In 2001, after cases of various cancers from missileers were reported—including cervical, thyroid, Hodgkin lymphoma, and non-Hodgkin lymphoma—the Air Force Institute for Operational Health conducted a site evaluation and sampling for possible chemical and biologic contaminants at their facilities. Results of all tests, the 2005 report said, did not demonstrate any levels above acceptable standards according to state and federal regulations. The survey concluded that launch control centers provide a safe and healthy working environment.

In 2005, following the release of the report, the USAF said “There is not sufficient evidence to consider the possibility of a cancer clustering to justify further investigation.” The research report noted, “[S]ometimes illnesses tend to occur by chance alone and it is not uncommon to see clustering or what has been referred to as ‘perceived clustering’ of conditions, especially when they occur in a close group of people or certain communities as in the military.”

On its website, though, the Air Force Medical Service now says that the findings from 2 decades ago may have changed.

The findings from the new study are not final. The USAF is continuing its investigation, including conducting an epidemiological study of cancers within the missile community. In the meantime, Air Force Global Strike Command Public Affairs says that, in response to the review panel’s recommendations, Gen. Bussiere has directed that facilities be deep cleaned regularly, signage denoting the presence of polychlorinated biphenyls be updated, and burning no longer allowed as a means of destroying classified materials inside the facilities.

Notably, the changes will also include improving communication and coordination between medical personnel and missile community members. Bussiere directed his staff to explore specifically assigning medical professionals to ICBM units, to have a better understanding of the environment and missions. He also ordered further engagement with personnel who work with known occupational hazards to collect more data and information. While awaiting the eventual replacement of the Minuteman III ICBM with the LGM-35A Sentinel, preventive maintenance and environmental upgrades will be prioritized and any upgrade or new piece of equipment will be “scrutinized for hazards.”

The USAF has also established a website to address the missileer community’s concerns.

In one of the first studies to examine this phenomenon, metabolically unhealthy obesity is associated with an increased risk, around 1.5-fold higher, of any obesity-related cancer, and an even higher risk, two- to threefold higher, for specific cancers, such as endometrial, liver, and renal cell cancers, compared with metabolically healthy normal weight.

Even in people with so-called “metabolically healthy” obesity, the risk for overall obesity-related cancer is increased, compared with normal-weight, metabolically healthy individuals; however, the associations here are weaker than in people with metabolically unhealthy obesity.

“The type of metabolic obesity phenotype is important when assessing obesity-related cancer risk,” lead researcher Ming Sun, PhD, from Lund University, Malmö, Sweden, said in an interview. “In general, metabolic aberrations further increased the obesity-induced cancer risk, suggesting that obesity and metabolic aberrations are useful targets for prevention.”

“This synergy means that when obesity and metabolic unhealth occur together, that’s particularly bad,” added Tanja Stocks, PhD, senior author, also of Lund University.

“But the data also highlight that even obesity and overweight alone comprise an increased risk of cancer,” Dr. Stocks noted.

Dr. Sun said the findings have important public health implications, suggesting that “a significant number of cancer cases could potentially be prevented by targeting the coexistence of metabolic problems and obesity, in particular for obesity-related cancers among men.”

The results will be presented as a poster by Dr. Sun at the European Congress on Obesity 2023, being held in Dublin, and have been published in the Journal of the National Cancer Institute.
 

Metabolically unhealthy obesity worst for cancer risks

Andrew G. Renehan, PhD, FRCS, professor of cancer studies and surgery, University of Manchester, England, welcomed the new work, saying it addresses the issue with very large study numbers. “[It] nicely demonstrates that there are clear examples where metabolically unhealthy overweight and obese phenotypes have increased cancer risk relative to [metabolically] healthy overweight and obese phenotypes,” he said.

“There is a clear need for clinically based research addressing these hypotheses ... but these studies will additionally need to factor in other dimensions such as the selection of treatment for metabolic aberrations, both medical and surgical, and the consequent metabolic control resulting from these interventions,” Dr. Renehan observed.

Vibhu Chittajallu, MD, a gastroenterologist based at University Hospitals Cleveland Medical Center, said it was beneficial to see another study further validating the association of obesity with the development of obesity-associated cancers.

“This is an interesting study [because it focuses] on the role of metabolic syndrome in obesity and how it affects the risk of development of obesity-associated cancers,” he said in an interview.

“I believe that the results of this study further strengthen the need for improved management of obesity and metabolic syndrome to reduce the risk of obesity-associated cancer formation that plays a role in preventable and premature deaths in adult patients with obesity.”
 

Synergy between metabolic aberrations and obesity, and cancer risk

Dr. Sun and colleagues note that obesity is an established risk factor for several cancers. It is often accompanied by metabolic aberrations, which have been a commonly proposed mechanism to link obesity with cancer. During the last decade, obesity with or without metabolic aberrations – commonly termed “metabolically unhealthy” or “healthy obesity” – has been extensively investigated in the cardiovascular field; however, studies regarding cancer are limited.

According to Dr. Sun, this new study is the first to look at the synergistic effect of unhealthy metabolism and body mass index – the latter was further categorized as normal weight (BMI < 25 kg/m2), overweight (BMI < 30) and obesity (BMI ≤ 30) – and the association with cancer risk, both overall and in relation to site-specific cancers.

Data were drawn from 797,193 European individuals (in Norway, Sweden, and Austria), of whom 23,630 developed an obesity-related cancer during the follow-up period. A metabolic score comprising mid-blood pressure, plasma glucose, and triglycerides was used to provide a measure of healthy or unhealthy metabolic status. Relative risks (hazard ratios) for overall and site-specific cancers were determined. Comparisons were made with metabolically healthy people of normal weight (effectively controls).

When different metabolic scores and BMIs were combined, participants fell into six categories: metabolically unhealthy obesity (6.8% of participants); metabolically healthy obesity (3.4%), metabolically unhealthy overweight (15.4%), metabolically healthy overweight (19.8%), metabolically unhealthy normal weight (12.5%), and metabolically healthy normal weight (42.0%).

Metabolically unhealthy women with obesity had a hazard ratio of 1.43 for overall obesity-related cancers, compared with metabolically healthy women of normal weight. Of particular note were risks of two cancer types in women with metabolically unhealthy obesity: renal cancer, with an HR of 2.43, and endometrial cancer, with an HR of 3.0, compared with controls.

Even in metabolically healthy women with obesity, compared with metabolically healthy women of normal weight, there was an increased risk of endometrial cancer, with an HR of 2.36.

“If you look at individual cancers, in particular endometrial cancer, this seems to be very much driven by obesity and not so much by the metabolic factor,” remarked Dr. Stocks.

In males, compared with metabolically healthy men of normal weight, metabolically unhealthy men with obesity had an overall obesity-related cancer risk HR of 1.91. Specifically, the risk of renal cell cancer was more than doubled, with an HR of 2.59. The HR for colon cancer was 1.85, and that for rectal cancer and pancreatic cancer was similar, both having HRs of 1.32.

Again, risk was lower in metabolically healthy men with obesity, although still higher than for metabolically healthy normal-weight men.

A version of this article first appeared on Medscape.com.

In one of the first studies to examine this phenomenon, metabolically unhealthy obesity is associated with an increased risk, around 1.5-fold higher, of any obesity-related cancer, and an even higher risk, two- to threefold higher, for specific cancers, such as endometrial, liver, and renal cell cancers, compared with metabolically healthy normal weight.

Even in people with so-called “metabolically healthy” obesity, the risk for overall obesity-related cancer is increased, compared with normal-weight, metabolically healthy individuals; however, the associations here are weaker than in people with metabolically unhealthy obesity.

“The type of metabolic obesity phenotype is important when assessing obesity-related cancer risk,” lead researcher Ming Sun, PhD, from Lund University, Malmö, Sweden, said in an interview. “In general, metabolic aberrations further increased the obesity-induced cancer risk, suggesting that obesity and metabolic aberrations are useful targets for prevention.”

“This synergy means that when obesity and metabolic unhealth occur together, that’s particularly bad,” added Tanja Stocks, PhD, senior author, also of Lund University.

“But the data also highlight that even obesity and overweight alone comprise an increased risk of cancer,” Dr. Stocks noted.

Dr. Sun said the findings have important public health implications, suggesting that “a significant number of cancer cases could potentially be prevented by targeting the coexistence of metabolic problems and obesity, in particular for obesity-related cancers among men.”

The results will be presented as a poster by Dr. Sun at the European Congress on Obesity 2023, being held in Dublin, and have been published in the Journal of the National Cancer Institute.
 

Metabolically unhealthy obesity worst for cancer risks

Andrew G. Renehan, PhD, FRCS, professor of cancer studies and surgery, University of Manchester, England, welcomed the new work, saying it addresses the issue with very large study numbers. “[It] nicely demonstrates that there are clear examples where metabolically unhealthy overweight and obese phenotypes have increased cancer risk relative to [metabolically] healthy overweight and obese phenotypes,” he said.

“There is a clear need for clinically based research addressing these hypotheses ... but these studies will additionally need to factor in other dimensions such as the selection of treatment for metabolic aberrations, both medical and surgical, and the consequent metabolic control resulting from these interventions,” Dr. Renehan observed.

Vibhu Chittajallu, MD, a gastroenterologist based at University Hospitals Cleveland Medical Center, said it was beneficial to see another study further validating the association of obesity with the development of obesity-associated cancers.

“This is an interesting study [because it focuses] on the role of metabolic syndrome in obesity and how it affects the risk of development of obesity-associated cancers,” he said in an interview.

“I believe that the results of this study further strengthen the need for improved management of obesity and metabolic syndrome to reduce the risk of obesity-associated cancer formation that plays a role in preventable and premature deaths in adult patients with obesity.”
 

Synergy between metabolic aberrations and obesity, and cancer risk

Dr. Sun and colleagues note that obesity is an established risk factor for several cancers. It is often accompanied by metabolic aberrations, which have been a commonly proposed mechanism to link obesity with cancer. During the last decade, obesity with or without metabolic aberrations – commonly termed “metabolically unhealthy” or “healthy obesity” – has been extensively investigated in the cardiovascular field; however, studies regarding cancer are limited.

According to Dr. Sun, this new study is the first to look at the synergistic effect of unhealthy metabolism and body mass index – the latter was further categorized as normal weight (BMI < 25 kg/m2), overweight (BMI < 30) and obesity (BMI ≤ 30) – and the association with cancer risk, both overall and in relation to site-specific cancers.

Data were drawn from 797,193 European individuals (in Norway, Sweden, and Austria), of whom 23,630 developed an obesity-related cancer during the follow-up period. A metabolic score comprising mid-blood pressure, plasma glucose, and triglycerides was used to provide a measure of healthy or unhealthy metabolic status. Relative risks (hazard ratios) for overall and site-specific cancers were determined. Comparisons were made with metabolically healthy people of normal weight (effectively controls).

When different metabolic scores and BMIs were combined, participants fell into six categories: metabolically unhealthy obesity (6.8% of participants); metabolically healthy obesity (3.4%), metabolically unhealthy overweight (15.4%), metabolically healthy overweight (19.8%), metabolically unhealthy normal weight (12.5%), and metabolically healthy normal weight (42.0%).

Metabolically unhealthy women with obesity had a hazard ratio of 1.43 for overall obesity-related cancers, compared with metabolically healthy women of normal weight. Of particular note were risks of two cancer types in women with metabolically unhealthy obesity: renal cancer, with an HR of 2.43, and endometrial cancer, with an HR of 3.0, compared with controls.

Even in metabolically healthy women with obesity, compared with metabolically healthy women of normal weight, there was an increased risk of endometrial cancer, with an HR of 2.36.

“If you look at individual cancers, in particular endometrial cancer, this seems to be very much driven by obesity and not so much by the metabolic factor,” remarked Dr. Stocks.

In males, compared with metabolically healthy men of normal weight, metabolically unhealthy men with obesity had an overall obesity-related cancer risk HR of 1.91. Specifically, the risk of renal cell cancer was more than doubled, with an HR of 2.59. The HR for colon cancer was 1.85, and that for rectal cancer and pancreatic cancer was similar, both having HRs of 1.32.

Again, risk was lower in metabolically healthy men with obesity, although still higher than for metabolically healthy normal-weight men.

A version of this article first appeared on Medscape.com.

In one of the first studies to examine this phenomenon, metabolically unhealthy obesity is associated with an increased risk, around 1.5-fold higher, of any obesity-related cancer, and an even higher risk, two- to threefold higher, for specific cancers, such as endometrial, liver, and renal cell cancers, compared with metabolically healthy normal weight.

Even in people with so-called “metabolically healthy” obesity, the risk for overall obesity-related cancer is increased, compared with normal-weight, metabolically healthy individuals; however, the associations here are weaker than in people with metabolically unhealthy obesity.

“The type of metabolic obesity phenotype is important when assessing obesity-related cancer risk,” lead researcher Ming Sun, PhD, from Lund University, Malmö, Sweden, said in an interview. “In general, metabolic aberrations further increased the obesity-induced cancer risk, suggesting that obesity and metabolic aberrations are useful targets for prevention.”

“This synergy means that when obesity and metabolic unhealth occur together, that’s particularly bad,” added Tanja Stocks, PhD, senior author, also of Lund University.

“But the data also highlight that even obesity and overweight alone comprise an increased risk of cancer,” Dr. Stocks noted.

Dr. Sun said the findings have important public health implications, suggesting that “a significant number of cancer cases could potentially be prevented by targeting the coexistence of metabolic problems and obesity, in particular for obesity-related cancers among men.”

The results will be presented as a poster by Dr. Sun at the European Congress on Obesity 2023, being held in Dublin, and have been published in the Journal of the National Cancer Institute.
 

Metabolically unhealthy obesity worst for cancer risks

Andrew G. Renehan, PhD, FRCS, professor of cancer studies and surgery, University of Manchester, England, welcomed the new work, saying it addresses the issue with very large study numbers. “[It] nicely demonstrates that there are clear examples where metabolically unhealthy overweight and obese phenotypes have increased cancer risk relative to [metabolically] healthy overweight and obese phenotypes,” he said.

“There is a clear need for clinically based research addressing these hypotheses ... but these studies will additionally need to factor in other dimensions such as the selection of treatment for metabolic aberrations, both medical and surgical, and the consequent metabolic control resulting from these interventions,” Dr. Renehan observed.

Vibhu Chittajallu, MD, a gastroenterologist based at University Hospitals Cleveland Medical Center, said it was beneficial to see another study further validating the association of obesity with the development of obesity-associated cancers.

“This is an interesting study [because it focuses] on the role of metabolic syndrome in obesity and how it affects the risk of development of obesity-associated cancers,” he said in an interview.

“I believe that the results of this study further strengthen the need for improved management of obesity and metabolic syndrome to reduce the risk of obesity-associated cancer formation that plays a role in preventable and premature deaths in adult patients with obesity.”
 

Synergy between metabolic aberrations and obesity, and cancer risk

Dr. Sun and colleagues note that obesity is an established risk factor for several cancers. It is often accompanied by metabolic aberrations, which have been a commonly proposed mechanism to link obesity with cancer. During the last decade, obesity with or without metabolic aberrations – commonly termed “metabolically unhealthy” or “healthy obesity” – has been extensively investigated in the cardiovascular field; however, studies regarding cancer are limited.

According to Dr. Sun, this new study is the first to look at the synergistic effect of unhealthy metabolism and body mass index – the latter was further categorized as normal weight (BMI < 25 kg/m2), overweight (BMI < 30) and obesity (BMI ≤ 30) – and the association with cancer risk, both overall and in relation to site-specific cancers.

Data were drawn from 797,193 European individuals (in Norway, Sweden, and Austria), of whom 23,630 developed an obesity-related cancer during the follow-up period. A metabolic score comprising mid-blood pressure, plasma glucose, and triglycerides was used to provide a measure of healthy or unhealthy metabolic status. Relative risks (hazard ratios) for overall and site-specific cancers were determined. Comparisons were made with metabolically healthy people of normal weight (effectively controls).

When different metabolic scores and BMIs were combined, participants fell into six categories: metabolically unhealthy obesity (6.8% of participants); metabolically healthy obesity (3.4%), metabolically unhealthy overweight (15.4%), metabolically healthy overweight (19.8%), metabolically unhealthy normal weight (12.5%), and metabolically healthy normal weight (42.0%).

Metabolically unhealthy women with obesity had a hazard ratio of 1.43 for overall obesity-related cancers, compared with metabolically healthy women of normal weight. Of particular note were risks of two cancer types in women with metabolically unhealthy obesity: renal cancer, with an HR of 2.43, and endometrial cancer, with an HR of 3.0, compared with controls.

Even in metabolically healthy women with obesity, compared with metabolically healthy women of normal weight, there was an increased risk of endometrial cancer, with an HR of 2.36.

“If you look at individual cancers, in particular endometrial cancer, this seems to be very much driven by obesity and not so much by the metabolic factor,” remarked Dr. Stocks.

In males, compared with metabolically healthy men of normal weight, metabolically unhealthy men with obesity had an overall obesity-related cancer risk HR of 1.91. Specifically, the risk of renal cell cancer was more than doubled, with an HR of 2.59. The HR for colon cancer was 1.85, and that for rectal cancer and pancreatic cancer was similar, both having HRs of 1.32.

Again, risk was lower in metabolically healthy men with obesity, although still higher than for metabolically healthy normal-weight men.

A version of this article first appeared on Medscape.com.

To the Editor:

Syringomas are common benign tumors of the eccrine sweat glands that usually manifest clinically as multiple flesh-colored papules. They are most commonly seen on the face, neck, and chest of adolescent girls. Syringomas may appear at any site of the body but are rare in the vulva. We present a case of a 51-year-old woman who was referred to the Division of Gynecologic Oncology at the University of Alabama at Birmingham for further management of a tumor carrying a differential diagnosis of vulvar syringoma vs microcystic adnexal carcinoma (MAC).

A 51-year-old woman presented to dermatology (G.G.) and was referred to the Division of Gynecologic Oncology at the University of Alabama at Birmingham for further management of possible vulvar syringoma vs MAC. The patient previously had been evaluated at an outside community practice due to dyspareunia, vulvar discomfort, and vulvar irregularities of 1 month’s duration. At that time, a small biopsy was performed, and the histologic differential diagnosis included syringoma vs an adnexal carcinoma. Consequently, she was referred to gynecologic oncology for further management.

Pelvic examination revealed multilobular nodular areas overlying the clitoral hood that extended down to the labia majora. The nodular processes did not involve the clitoris, labia minora, or perineum. A mobile isolated lymph node measuring 2.0×1.0 cm in the right inguinal area also was noted. The patient’s clinical history was notable for right breast carcinoma treated with a right mastectomy with axillary lymph node dissection that showed metastatic disease. She also underwent adjuvant chemotherapy with paclitaxel and doxorubicin for breast carcinoma.

After discussing the diagnostic differential and treatment options, the patient elected to undergo a bilateral partial radical vulvectomy with reconstruction and resection of the right inguinal lymph node. Gross examination of the vulvectomy specimen showed multiple flesh-colored papules (FIGURE 1). Histologic examination revealed a neoplasm with sweat gland differentiation that was broad and poorly circumscribed but confined to the dermis (FIGURES 2A and 2B). The neoplasm was composed of epithelial cells that formed ductlike structures, lined by 2 layers of cuboidal epithelium within a fibrous stroma (FIGURE 2C). A toluidine blue special stain was performed and demonstrated an increased amount of mast cells in the tissue (FIGURE 3). Immunohistochemical stains for gross cystic disease fluid protein, estrogen receptor (ER), and progesterone receptor (PR) were negative in the tumor cells. The lack of cytologic atypia, perineural invasion, and deep infiltration into the subcutis favored a syringoma. One month later, the case was presented at the Tumor Board Conference at the University of Alabama at Birmingham where a final diagnosis of vulvar syringoma was agreed upon and discussed with the patient. At that time, no recurrence was evident and follow-up was recommended.

Syringomas are benign tumors of the sweat glands that are fairly common and appear to have a predilection for women. Although most of the literature classifies them as eccrine neoplasms, the term syringoma can be used to describe neoplasms of either apocrine or eccrine lineage.¹ To rule out an apocrine lineage of the tumor in our patient, we performed immunohistochemistry for gross cystic disease fluid protein, a marker of apocrine differentiation. This stain highlighted normal apocrine glands that were not involved in the tumor proliferation.

Syringomas may occur at any site on the body but are prone to occur on the periorbital area, especially the eyelids.¹ Some of the atypical locations for a syringoma include the anterior neck, chest, abdomen, genitals, axillae, groin, and buttocks.² Vulvar syringomas were first reported by Carneiro³ in 1971 as usually affecting adolescent girls and middle-aged women. There have been approximately 40 reported cases affecting women aged 8 to 78 years.^4,5 Vulvar syringomas classically appear as firm or soft, flesh-colored to transparent, papular lesions. The 2 other clinical variants are miliumlike, whitish, cystic papules as well as lichenoid papules.⁶ Pérez-Bustillo et al⁵ reported a case of the lichenoid papule variant on the labia majora of a 78-year-old woman who presented with intermittent vulvar pruritus of 4 years’ duration. Due to this patient’s 9-year history of urinary incontinence, the lesions had been misdiagnosed as irritant dermatitis and associated lichen simplex chronicus (LSC). This case is a reminder to consider vulvar syringoma in patients with LSC who respond poorly to oral antihistamines and topical steroids.⁵ Rarely, multiple clinical variants may coexist. In a case reported by Dereli et al,⁷ a 19-year-old woman presented with concurrent classical and miliumlike forms of vulvar syringoma.

Vulvar syringomas usually present as multiple lesions involving both sides of the labia majora; however, Blasdale and McLelland⁸ reported a single isolated syringoma of the vulva on the anterior right labia minora that measured 1.0×0.5 cm, leading the lesion to be described as a giant syringoma.

Vulvar syringomas usually are asymptomatic and noticed during routine gynecologic examination. Therefore, it is believed that they likely are underdiagnosed.⁵ When symptomatic, they commonly present with constant⁹ or intermittent⁵ pruritus, which may intensify during menstruation, pregnancy, and summertime.^6,10-12 Gerdsen et al¹⁰ documented a 27-year-old woman who presented with a 2-year history of pruritic vulvar skin lesions that became exacerbated during menstruation, which raised the possibility of cyclical hormonal changes being responsible for periodic exacerbation of vulvar pruritus during menstruation. In addition, patients may experience an increase in size and number of the lesions during pregnancy. Bal et al¹¹ reported a 24-year-old primigravida with vulvar papular lesions that intensified during pregnancy. She had experienced intermittent vulvar pruritus for 12 years but had no change in symptoms during menstruation.¹¹ Few studies have attempted to evaluate the presence of ER and PR in the syringomas. A study of 9 nonvulvar syringomas by Wallace and Smoller¹³ showed ER positivity in 1 case and PR positivity in 8 cases, lending support to the hormonal theory; however, in another case series of 15 vulvar syringomas, Huang et al⁶ failed to show ER and PR expression by immunohistochemical staining. A case report published 3 years earlier documented the first case of PR positivity on a vulvar syringoma.¹⁴ Our patient also was negative for ER and PR, which suggested that hormonal status is important in some but not all syringomas.

Patients with vulvar syringomas also might have coexisting extragenital syringomas in the neck,⁴ eyelids,^6,7,10 and periorbital area,⁶ and thorough examination of the body is essential. If an extragenital syringoma is diagnosed, a vulvar syringoma should be considered, especially when the patient presents with unexplained genital symptoms. Although no proven hereditary transmission pattern has been established, family history of syringomas has been established in several cases.¹⁵ In a case series reported by Huang et al,⁶ 4 of 18 patients reported a family history of periorbital syringomas. In our case, the patient did not report a family history of syringomas.

The differential diagnosis of vulvar lesions with pruritus is broad and includes Fox-Fordyce disease, lichen planus, LSC, epidermal cysts, senile angiomas, dystrophic calcinosis, xanthomas, steatocytomas, soft fibromas, condyloma acuminatum, and candidiasis. Vulvar syringomas might have a nonspecific appearance, and histologic examination is essential to confirm the diagnosis and rule out any malignant process such as MAC, vulvar intraepithelial neoplasia, extramammary Paget disease, or other glandular neoplasms of the vulva.

Microcystic adnexal carcinoma was first reported in 1982 by Goldstein et al¹⁶ as a locally aggressive neoplasm that can be confused with benign adnexal neoplasms, particularly desmoplastic trichoepithelioma, trichoadenoma, and syringoma. Microcystic adnexal carcinomas present as slow-growing, flesh-colored papules that may resemble syringomas and appear in similar body sites. Histologic examination is essential to differentiate between these two entities. Syringomas are tumors confined to the dermis and are composed of multiple small ducts lined by 2 layers of cuboidal epithelium within a dense fibrous stroma. Unlike syringomas, MACs usually infiltrate diffusely into the dermis and subcutis and may extend into the underlying muscle. Although bland cytologic features predominate, perineural invasion frequently is present in MACs. A potential pitfall of misdiagnosis can be caused by a superficial biopsy that may reveal benign histologic appearance, particularly in the upper level of the tumor where it may be confused with a syringoma or a benign follicular neoplasm.¹⁷

The initial biopsy performed on our patient was possibly not deep enough to render an unequivocal diagnosis and therefore bilateral partial radical vulvectomy was considered. After surgery, histologic examination of the resection specimen revealed a poorly circumscribed tumor confined to the dermis. The tumor was broad and the lack of deep infiltration into the subcutis and perineural invasion favored a syringoma (FIGURES 2A and 2B). These findings were consistent with case reports that documented syringomas as being more wide than deep on microscopic examination, whereas the opposite pertained to MAC.¹⁸ Cases of plaque-type syringomas that initially were misdiagnosed as MACs also have been reported.¹⁹ Because misdiagnosis may affect the treatment plan and potentially result in unnecessary surgery, caution should be taken when differentiating between these two entities. When a definitive diagnosis cannot be rendered on a superficial biopsy, a recommendation should be made for a deeper biopsy sampling the subcutis.

For the majority of the patients with vulvar syringomas, treatment is seldom required due to their asymptomatic nature; however, patients who present with symptoms usually report pruritus of variable intensities and patterns. A standardized treatment does not exist for vulvar syringomas, and oral or topical treatment might be used as an initial approach. Commonly prescribed medications with variable results include topical corticosteroids, oral antihistamines, and topical retinoids. In a case reported by Iwao et al,²⁰ vulvar syringomas were successfully treated with tranilast, which has anti-inflammatory and immunomodulatory effects. This medication could have a possible dual action—inhibiting the release of chemical mediators from the mast cells and inhibiting the release of IL-1β from the eccrine duct, which could suppress the proliferation of stromal connective tissue. Our case was stained with toluidine blue and showed an increased number of mast cells in the tissue (FIGURE 3).Patients who are unresponsive to tranilast or have extensive disease resulting in cosmetic disfigurement might benefit from more invasive treatment methods including a variety of lasers, cryotherapy, electrosurgery, and excision. Excisions should include the entire tumor to avoid recurrence. In a case reported by Garman and Metry,²¹ the lesions were surgically excised using small 2- to 3-mm punches; however, several weeks later the lesions recurred. Our patient presented with a 1-month evolution of dyspareunia, vulvar discomfort, and vulvar irregularities that were probably not treated with oral or topical medications before being referred for surgery.

We report a case of a vulvar syringoma that presented diagnostic challenges in the initial biopsy, which prevented the exclusion of an MAC. After partial radical vulvectomy, histologic examination was more definitive, showing lack of deep infiltration into the subcutis or perineural invasion that are commonly seen in MAC. This case is an example of a notable pitfall in the diagnosis of vulvar syringoma on a limited biopsy leading to overtreatment. Raising awareness of this entity is the only modality to prevent misdiagnosis. We encourage reporting of further cases of syringomas, particularly those with atypical locations or patterns that may cause diagnostic problems. ●

To the Editor:

Syringomas are common benign tumors of the eccrine sweat glands that usually manifest clinically as multiple flesh-colored papules. They are most commonly seen on the face, neck, and chest of adolescent girls. Syringomas may appear at any site of the body but are rare in the vulva. We present a case of a 51-year-old woman who was referred to the Division of Gynecologic Oncology at the University of Alabama at Birmingham for further management of a tumor carrying a differential diagnosis of vulvar syringoma vs microcystic adnexal carcinoma (MAC).

A 51-year-old woman presented to dermatology (G.G.) and was referred to the Division of Gynecologic Oncology at the University of Alabama at Birmingham for further management of possible vulvar syringoma vs MAC. The patient previously had been evaluated at an outside community practice due to dyspareunia, vulvar discomfort, and vulvar irregularities of 1 month’s duration. At that time, a small biopsy was performed, and the histologic differential diagnosis included syringoma vs an adnexal carcinoma. Consequently, she was referred to gynecologic oncology for further management.

Pelvic examination revealed multilobular nodular areas overlying the clitoral hood that extended down to the labia majora. The nodular processes did not involve the clitoris, labia minora, or perineum. A mobile isolated lymph node measuring 2.0×1.0 cm in the right inguinal area also was noted. The patient’s clinical history was notable for right breast carcinoma treated with a right mastectomy with axillary lymph node dissection that showed metastatic disease. She also underwent adjuvant chemotherapy with paclitaxel and doxorubicin for breast carcinoma.

After discussing the diagnostic differential and treatment options, the patient elected to undergo a bilateral partial radical vulvectomy with reconstruction and resection of the right inguinal lymph node. Gross examination of the vulvectomy specimen showed multiple flesh-colored papules (FIGURE 1). Histologic examination revealed a neoplasm with sweat gland differentiation that was broad and poorly circumscribed but confined to the dermis (FIGURES 2A and 2B). The neoplasm was composed of epithelial cells that formed ductlike structures, lined by 2 layers of cuboidal epithelium within a fibrous stroma (FIGURE 2C). A toluidine blue special stain was performed and demonstrated an increased amount of mast cells in the tissue (FIGURE 3). Immunohistochemical stains for gross cystic disease fluid protein, estrogen receptor (ER), and progesterone receptor (PR) were negative in the tumor cells. The lack of cytologic atypia, perineural invasion, and deep infiltration into the subcutis favored a syringoma. One month later, the case was presented at the Tumor Board Conference at the University of Alabama at Birmingham where a final diagnosis of vulvar syringoma was agreed upon and discussed with the patient. At that time, no recurrence was evident and follow-up was recommended.

Syringomas are benign tumors of the sweat glands that are fairly common and appear to have a predilection for women. Although most of the literature classifies them as eccrine neoplasms, the term syringoma can be used to describe neoplasms of either apocrine or eccrine lineage.¹ To rule out an apocrine lineage of the tumor in our patient, we performed immunohistochemistry for gross cystic disease fluid protein, a marker of apocrine differentiation. This stain highlighted normal apocrine glands that were not involved in the tumor proliferation.

Syringomas may occur at any site on the body but are prone to occur on the periorbital area, especially the eyelids.¹ Some of the atypical locations for a syringoma include the anterior neck, chest, abdomen, genitals, axillae, groin, and buttocks.² Vulvar syringomas were first reported by Carneiro³ in 1971 as usually affecting adolescent girls and middle-aged women. There have been approximately 40 reported cases affecting women aged 8 to 78 years.^4,5 Vulvar syringomas classically appear as firm or soft, flesh-colored to transparent, papular lesions. The 2 other clinical variants are miliumlike, whitish, cystic papules as well as lichenoid papules.⁶ Pérez-Bustillo et al⁵ reported a case of the lichenoid papule variant on the labia majora of a 78-year-old woman who presented with intermittent vulvar pruritus of 4 years’ duration. Due to this patient’s 9-year history of urinary incontinence, the lesions had been misdiagnosed as irritant dermatitis and associated lichen simplex chronicus (LSC). This case is a reminder to consider vulvar syringoma in patients with LSC who respond poorly to oral antihistamines and topical steroids.⁵ Rarely, multiple clinical variants may coexist. In a case reported by Dereli et al,⁷ a 19-year-old woman presented with concurrent classical and miliumlike forms of vulvar syringoma.

Vulvar syringomas usually present as multiple lesions involving both sides of the labia majora; however, Blasdale and McLelland⁸ reported a single isolated syringoma of the vulva on the anterior right labia minora that measured 1.0×0.5 cm, leading the lesion to be described as a giant syringoma.

Vulvar syringomas usually are asymptomatic and noticed during routine gynecologic examination. Therefore, it is believed that they likely are underdiagnosed.⁵ When symptomatic, they commonly present with constant⁹ or intermittent⁵ pruritus, which may intensify during menstruation, pregnancy, and summertime.^6,10-12 Gerdsen et al¹⁰ documented a 27-year-old woman who presented with a 2-year history of pruritic vulvar skin lesions that became exacerbated during menstruation, which raised the possibility of cyclical hormonal changes being responsible for periodic exacerbation of vulvar pruritus during menstruation. In addition, patients may experience an increase in size and number of the lesions during pregnancy. Bal et al¹¹ reported a 24-year-old primigravida with vulvar papular lesions that intensified during pregnancy. She had experienced intermittent vulvar pruritus for 12 years but had no change in symptoms during menstruation.¹¹ Few studies have attempted to evaluate the presence of ER and PR in the syringomas. A study of 9 nonvulvar syringomas by Wallace and Smoller¹³ showed ER positivity in 1 case and PR positivity in 8 cases, lending support to the hormonal theory; however, in another case series of 15 vulvar syringomas, Huang et al⁶ failed to show ER and PR expression by immunohistochemical staining. A case report published 3 years earlier documented the first case of PR positivity on a vulvar syringoma.¹⁴ Our patient also was negative for ER and PR, which suggested that hormonal status is important in some but not all syringomas.

Patients with vulvar syringomas also might have coexisting extragenital syringomas in the neck,⁴ eyelids,^6,7,10 and periorbital area,⁶ and thorough examination of the body is essential. If an extragenital syringoma is diagnosed, a vulvar syringoma should be considered, especially when the patient presents with unexplained genital symptoms. Although no proven hereditary transmission pattern has been established, family history of syringomas has been established in several cases.¹⁵ In a case series reported by Huang et al,⁶ 4 of 18 patients reported a family history of periorbital syringomas. In our case, the patient did not report a family history of syringomas.

The differential diagnosis of vulvar lesions with pruritus is broad and includes Fox-Fordyce disease, lichen planus, LSC, epidermal cysts, senile angiomas, dystrophic calcinosis, xanthomas, steatocytomas, soft fibromas, condyloma acuminatum, and candidiasis. Vulvar syringomas might have a nonspecific appearance, and histologic examination is essential to confirm the diagnosis and rule out any malignant process such as MAC, vulvar intraepithelial neoplasia, extramammary Paget disease, or other glandular neoplasms of the vulva.

Microcystic adnexal carcinoma was first reported in 1982 by Goldstein et al¹⁶ as a locally aggressive neoplasm that can be confused with benign adnexal neoplasms, particularly desmoplastic trichoepithelioma, trichoadenoma, and syringoma. Microcystic adnexal carcinomas present as slow-growing, flesh-colored papules that may resemble syringomas and appear in similar body sites. Histologic examination is essential to differentiate between these two entities. Syringomas are tumors confined to the dermis and are composed of multiple small ducts lined by 2 layers of cuboidal epithelium within a dense fibrous stroma. Unlike syringomas, MACs usually infiltrate diffusely into the dermis and subcutis and may extend into the underlying muscle. Although bland cytologic features predominate, perineural invasion frequently is present in MACs. A potential pitfall of misdiagnosis can be caused by a superficial biopsy that may reveal benign histologic appearance, particularly in the upper level of the tumor where it may be confused with a syringoma or a benign follicular neoplasm.¹⁷

The initial biopsy performed on our patient was possibly not deep enough to render an unequivocal diagnosis and therefore bilateral partial radical vulvectomy was considered. After surgery, histologic examination of the resection specimen revealed a poorly circumscribed tumor confined to the dermis. The tumor was broad and the lack of deep infiltration into the subcutis and perineural invasion favored a syringoma (FIGURES 2A and 2B). These findings were consistent with case reports that documented syringomas as being more wide than deep on microscopic examination, whereas the opposite pertained to MAC.¹⁸ Cases of plaque-type syringomas that initially were misdiagnosed as MACs also have been reported.¹⁹ Because misdiagnosis may affect the treatment plan and potentially result in unnecessary surgery, caution should be taken when differentiating between these two entities. When a definitive diagnosis cannot be rendered on a superficial biopsy, a recommendation should be made for a deeper biopsy sampling the subcutis.

For the majority of the patients with vulvar syringomas, treatment is seldom required due to their asymptomatic nature; however, patients who present with symptoms usually report pruritus of variable intensities and patterns. A standardized treatment does not exist for vulvar syringomas, and oral or topical treatment might be used as an initial approach. Commonly prescribed medications with variable results include topical corticosteroids, oral antihistamines, and topical retinoids. In a case reported by Iwao et al,²⁰ vulvar syringomas were successfully treated with tranilast, which has anti-inflammatory and immunomodulatory effects. This medication could have a possible dual action—inhibiting the release of chemical mediators from the mast cells and inhibiting the release of IL-1β from the eccrine duct, which could suppress the proliferation of stromal connective tissue. Our case was stained with toluidine blue and showed an increased number of mast cells in the tissue (FIGURE 3).Patients who are unresponsive to tranilast or have extensive disease resulting in cosmetic disfigurement might benefit from more invasive treatment methods including a variety of lasers, cryotherapy, electrosurgery, and excision. Excisions should include the entire tumor to avoid recurrence. In a case reported by Garman and Metry,²¹ the lesions were surgically excised using small 2- to 3-mm punches; however, several weeks later the lesions recurred. Our patient presented with a 1-month evolution of dyspareunia, vulvar discomfort, and vulvar irregularities that were probably not treated with oral or topical medications before being referred for surgery.

We report a case of a vulvar syringoma that presented diagnostic challenges in the initial biopsy, which prevented the exclusion of an MAC. After partial radical vulvectomy, histologic examination was more definitive, showing lack of deep infiltration into the subcutis or perineural invasion that are commonly seen in MAC. This case is an example of a notable pitfall in the diagnosis of vulvar syringoma on a limited biopsy leading to overtreatment. Raising awareness of this entity is the only modality to prevent misdiagnosis. We encourage reporting of further cases of syringomas, particularly those with atypical locations or patterns that may cause diagnostic problems. ●

To the Editor:

Syringomas are common benign tumors of the eccrine sweat glands that usually manifest clinically as multiple flesh-colored papules. They are most commonly seen on the face, neck, and chest of adolescent girls. Syringomas may appear at any site of the body but are rare in the vulva. We present a case of a 51-year-old woman who was referred to the Division of Gynecologic Oncology at the University of Alabama at Birmingham for further management of a tumor carrying a differential diagnosis of vulvar syringoma vs microcystic adnexal carcinoma (MAC).

A 51-year-old woman presented to dermatology (G.G.) and was referred to the Division of Gynecologic Oncology at the University of Alabama at Birmingham for further management of possible vulvar syringoma vs MAC. The patient previously had been evaluated at an outside community practice due to dyspareunia, vulvar discomfort, and vulvar irregularities of 1 month’s duration. At that time, a small biopsy was performed, and the histologic differential diagnosis included syringoma vs an adnexal carcinoma. Consequently, she was referred to gynecologic oncology for further management.

Pelvic examination revealed multilobular nodular areas overlying the clitoral hood that extended down to the labia majora. The nodular processes did not involve the clitoris, labia minora, or perineum. A mobile isolated lymph node measuring 2.0×1.0 cm in the right inguinal area also was noted. The patient’s clinical history was notable for right breast carcinoma treated with a right mastectomy with axillary lymph node dissection that showed metastatic disease. She also underwent adjuvant chemotherapy with paclitaxel and doxorubicin for breast carcinoma.

After discussing the diagnostic differential and treatment options, the patient elected to undergo a bilateral partial radical vulvectomy with reconstruction and resection of the right inguinal lymph node. Gross examination of the vulvectomy specimen showed multiple flesh-colored papules (FIGURE 1). Histologic examination revealed a neoplasm with sweat gland differentiation that was broad and poorly circumscribed but confined to the dermis (FIGURES 2A and 2B). The neoplasm was composed of epithelial cells that formed ductlike structures, lined by 2 layers of cuboidal epithelium within a fibrous stroma (FIGURE 2C). A toluidine blue special stain was performed and demonstrated an increased amount of mast cells in the tissue (FIGURE 3). Immunohistochemical stains for gross cystic disease fluid protein, estrogen receptor (ER), and progesterone receptor (PR) were negative in the tumor cells. The lack of cytologic atypia, perineural invasion, and deep infiltration into the subcutis favored a syringoma. One month later, the case was presented at the Tumor Board Conference at the University of Alabama at Birmingham where a final diagnosis of vulvar syringoma was agreed upon and discussed with the patient. At that time, no recurrence was evident and follow-up was recommended.

Syringomas are benign tumors of the sweat glands that are fairly common and appear to have a predilection for women. Although most of the literature classifies them as eccrine neoplasms, the term syringoma can be used to describe neoplasms of either apocrine or eccrine lineage.¹ To rule out an apocrine lineage of the tumor in our patient, we performed immunohistochemistry for gross cystic disease fluid protein, a marker of apocrine differentiation. This stain highlighted normal apocrine glands that were not involved in the tumor proliferation.

Syringomas may occur at any site on the body but are prone to occur on the periorbital area, especially the eyelids.¹ Some of the atypical locations for a syringoma include the anterior neck, chest, abdomen, genitals, axillae, groin, and buttocks.² Vulvar syringomas were first reported by Carneiro³ in 1971 as usually affecting adolescent girls and middle-aged women. There have been approximately 40 reported cases affecting women aged 8 to 78 years.^4,5 Vulvar syringomas classically appear as firm or soft, flesh-colored to transparent, papular lesions. The 2 other clinical variants are miliumlike, whitish, cystic papules as well as lichenoid papules.⁶ Pérez-Bustillo et al⁵ reported a case of the lichenoid papule variant on the labia majora of a 78-year-old woman who presented with intermittent vulvar pruritus of 4 years’ duration. Due to this patient’s 9-year history of urinary incontinence, the lesions had been misdiagnosed as irritant dermatitis and associated lichen simplex chronicus (LSC). This case is a reminder to consider vulvar syringoma in patients with LSC who respond poorly to oral antihistamines and topical steroids.⁵ Rarely, multiple clinical variants may coexist. In a case reported by Dereli et al,⁷ a 19-year-old woman presented with concurrent classical and miliumlike forms of vulvar syringoma.

Vulvar syringomas usually present as multiple lesions involving both sides of the labia majora; however, Blasdale and McLelland⁸ reported a single isolated syringoma of the vulva on the anterior right labia minora that measured 1.0×0.5 cm, leading the lesion to be described as a giant syringoma.

Vulvar syringomas usually are asymptomatic and noticed during routine gynecologic examination. Therefore, it is believed that they likely are underdiagnosed.⁵ When symptomatic, they commonly present with constant⁹ or intermittent⁵ pruritus, which may intensify during menstruation, pregnancy, and summertime.^6,10-12 Gerdsen et al¹⁰ documented a 27-year-old woman who presented with a 2-year history of pruritic vulvar skin lesions that became exacerbated during menstruation, which raised the possibility of cyclical hormonal changes being responsible for periodic exacerbation of vulvar pruritus during menstruation. In addition, patients may experience an increase in size and number of the lesions during pregnancy. Bal et al¹¹ reported a 24-year-old primigravida with vulvar papular lesions that intensified during pregnancy. She had experienced intermittent vulvar pruritus for 12 years but had no change in symptoms during menstruation.¹¹ Few studies have attempted to evaluate the presence of ER and PR in the syringomas. A study of 9 nonvulvar syringomas by Wallace and Smoller¹³ showed ER positivity in 1 case and PR positivity in 8 cases, lending support to the hormonal theory; however, in another case series of 15 vulvar syringomas, Huang et al⁶ failed to show ER and PR expression by immunohistochemical staining. A case report published 3 years earlier documented the first case of PR positivity on a vulvar syringoma.¹⁴ Our patient also was negative for ER and PR, which suggested that hormonal status is important in some but not all syringomas.

Patients with vulvar syringomas also might have coexisting extragenital syringomas in the neck,⁴ eyelids,^6,7,10 and periorbital area,⁶ and thorough examination of the body is essential. If an extragenital syringoma is diagnosed, a vulvar syringoma should be considered, especially when the patient presents with unexplained genital symptoms. Although no proven hereditary transmission pattern has been established, family history of syringomas has been established in several cases.¹⁵ In a case series reported by Huang et al,⁶ 4 of 18 patients reported a family history of periorbital syringomas. In our case, the patient did not report a family history of syringomas.

The differential diagnosis of vulvar lesions with pruritus is broad and includes Fox-Fordyce disease, lichen planus, LSC, epidermal cysts, senile angiomas, dystrophic calcinosis, xanthomas, steatocytomas, soft fibromas, condyloma acuminatum, and candidiasis. Vulvar syringomas might have a nonspecific appearance, and histologic examination is essential to confirm the diagnosis and rule out any malignant process such as MAC, vulvar intraepithelial neoplasia, extramammary Paget disease, or other glandular neoplasms of the vulva.

Microcystic adnexal carcinoma was first reported in 1982 by Goldstein et al¹⁶ as a locally aggressive neoplasm that can be confused with benign adnexal neoplasms, particularly desmoplastic trichoepithelioma, trichoadenoma, and syringoma. Microcystic adnexal carcinomas present as slow-growing, flesh-colored papules that may resemble syringomas and appear in similar body sites. Histologic examination is essential to differentiate between these two entities. Syringomas are tumors confined to the dermis and are composed of multiple small ducts lined by 2 layers of cuboidal epithelium within a dense fibrous stroma. Unlike syringomas, MACs usually infiltrate diffusely into the dermis and subcutis and may extend into the underlying muscle. Although bland cytologic features predominate, perineural invasion frequently is present in MACs. A potential pitfall of misdiagnosis can be caused by a superficial biopsy that may reveal benign histologic appearance, particularly in the upper level of the tumor where it may be confused with a syringoma or a benign follicular neoplasm.¹⁷

The initial biopsy performed on our patient was possibly not deep enough to render an unequivocal diagnosis and therefore bilateral partial radical vulvectomy was considered. After surgery, histologic examination of the resection specimen revealed a poorly circumscribed tumor confined to the dermis. The tumor was broad and the lack of deep infiltration into the subcutis and perineural invasion favored a syringoma (FIGURES 2A and 2B). These findings were consistent with case reports that documented syringomas as being more wide than deep on microscopic examination, whereas the opposite pertained to MAC.¹⁸ Cases of plaque-type syringomas that initially were misdiagnosed as MACs also have been reported.¹⁹ Because misdiagnosis may affect the treatment plan and potentially result in unnecessary surgery, caution should be taken when differentiating between these two entities. When a definitive diagnosis cannot be rendered on a superficial biopsy, a recommendation should be made for a deeper biopsy sampling the subcutis.

For the majority of the patients with vulvar syringomas, treatment is seldom required due to their asymptomatic nature; however, patients who present with symptoms usually report pruritus of variable intensities and patterns. A standardized treatment does not exist for vulvar syringomas, and oral or topical treatment might be used as an initial approach. Commonly prescribed medications with variable results include topical corticosteroids, oral antihistamines, and topical retinoids. In a case reported by Iwao et al,²⁰ vulvar syringomas were successfully treated with tranilast, which has anti-inflammatory and immunomodulatory effects. This medication could have a possible dual action—inhibiting the release of chemical mediators from the mast cells and inhibiting the release of IL-1β from the eccrine duct, which could suppress the proliferation of stromal connective tissue. Our case was stained with toluidine blue and showed an increased number of mast cells in the tissue (FIGURE 3).Patients who are unresponsive to tranilast or have extensive disease resulting in cosmetic disfigurement might benefit from more invasive treatment methods including a variety of lasers, cryotherapy, electrosurgery, and excision. Excisions should include the entire tumor to avoid recurrence. In a case reported by Garman and Metry,²¹ the lesions were surgically excised using small 2- to 3-mm punches; however, several weeks later the lesions recurred. Our patient presented with a 1-month evolution of dyspareunia, vulvar discomfort, and vulvar irregularities that were probably not treated with oral or topical medications before being referred for surgery.

We report a case of a vulvar syringoma that presented diagnostic challenges in the initial biopsy, which prevented the exclusion of an MAC. After partial radical vulvectomy, histologic examination was more definitive, showing lack of deep infiltration into the subcutis or perineural invasion that are commonly seen in MAC. This case is an example of a notable pitfall in the diagnosis of vulvar syringoma on a limited biopsy leading to overtreatment. Raising awareness of this entity is the only modality to prevent misdiagnosis. We encourage reporting of further cases of syringomas, particularly those with atypical locations or patterns that may cause diagnostic problems. ●

Bariatric surgery for obesity is associated with a reduced risk of developing breast cancer, new data suggest.

In a matched cohort study of more than 69,000 Canadian women, risk for incident breast cancer at 1 year was 40% higher among women who had not undergone bariatric surgery, compared with those who had. The risk remained elevated through 5 years of follow-up.

The findings were “definitely a bit surprising,” study author Aristithes G. Doumouras, MD, MPH, assistant professor of surgery at McMaster University, Hamilton, Ont., said in an interview. “The patients that underwent bariatric surgery had better cancer outcomes than patients who weighed less than they did, so it showed that there was more at play than just weight loss. This effect was durable [and] shows how powerful the surgery is, [as well as] the fact that we haven’t even explored all of its effects.”

The study was published online in JAMA Surgery.
 

Protective association

To determine whether there is a residual risk for breast cancer following bariatric surgery for obesity, the investigators analyzed clinical and administrative data collected between 2010 and 2016 in Ontario. They retrospectively matched women with obesity who underwent bariatric surgery with women without a history of bariatric surgery. Participants were matched by age and breast cancer screening status. Covariates included diabetes status, neighborhood income quintile, and measures of health care use. The population included 69,260 women (mean age, 45 years).

Among participants who underwent bariatric surgery for obesity, baseline body mass index was greater than 35 for those with related comorbid conditions, and BMI was greater than 40 for those without comorbid conditions. The investigators categorized nonsurgical control patients in accordance with the following four BMI categories: less than 25, 25-29, 30-34, and greater than or equal to 35. Each control group, as well as the surgical group, included 13,852 women.

Participants in the surgical group were followed for 5 years after bariatric surgery. Those in the nonsurgical group were followed for 5 years after the index date (that is, the date of BMI measurement).

In the overall population, 659 cases of breast cancer were diagnosed in the overall population (0.95%) during the study period. This total included 103 (0.74%) cancers in the surgical cohort; 128 (0.92%) in the group with BMI less than 25; 143 (1.03%) among those with BMI 25-29; 150 (1.08%) in the group with BMI 30-34; and 135 (0.97%) among those with BMI greater than or equal to 35.

Most cancers were stage I. There were 65 cases among those with BMI less than 25; 76 for those with BMI of 25-29; 65 for BMI of 30-34; 67 for BMI greater than or equal to 35, and 60 for the surgery group.

Most tumors were of medium grade and were estrogen receptor positive, progesterone receptor positive, and ERBB2 negative. No significant differences were observed across the groups for stage, grade, or hormone status.

There was an increased hazard for incident breast cancer in the nonsurgical group, compared with the postsurgical group after washout periods of 1 year (hazard ratio, 1.40), 2 years (HR, 1.31), and 5 years (HR, 1.38).

In a comparison of the postsurgical cohort with the nonsurgical cohort with BMI less than 25, the hazard of incident breast cancer was not significantly different for any of the washout periods, but there was a reduced hazard for incident breast cancer among postsurgical patients than among nonsurgical patients in all high BMI categories (BMI ≥ 25).

“Taken together, these results demonstrate that the protective association between substantial weight loss via bariatric surgery and breast cancer risk is sustained after 5 years following surgery and that it is associated with a baseline risk similar to that of women with BMI less than 25,” the investigators write.

Nevertheless, Dr. Doumouras said “the interaction between the surgery and individuals is poorly studied, and this level of personalized medicine is simply not there yet. We are working on developing a prospective cohort that has genetic, protein, and microbiome [data] to help answer these questions.”

There are not enough women in subpopulations such as BRCA carriers to study at this point, he added. “This is where more patients and time will really help the research process.”
 

A universal benefit?

“Although these findings are important overall for the general population at risk for breast cancer, we raise an important caveat: The benefit of surgical weight loss may not be universal,” write Justin B. Dimick, MD, MPH, surgical innovation editor for JAMA Surgery, and Melissa L. Pilewskie, MD, both of the University of Michigan, Ann Arbor, in an accompanying commentary.

“In addition to lifestyle factors, several nonmodifiable risk factors, such as a genetic predisposition, strong family history, personal history of a high-risk breast lesion, or history of chest wall radiation, impart significant elevation in risk, and the data remain mixed on the impact of weight loss for individuals in these high-risk cohorts,” they add.

“Further study to elucidate the underlying mechanism associated with obesity, weight loss, and breast cancer risk should help guide strategies for risk reduction that are specific to unique high-risk cohorts, because modifiable risk factors may not portend the same benefit among all groups.”

Commenting on the findings, Stephen Edge, MD, breast surgeon and vice president for system quality and outcomes at Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., said, “The importance of this study is that it shows that weight loss in midlife can reduce breast cancer risk back to or even below the risk of similar people who were not obese. This has major implications for counseling women.”

The investigators did not have information on the extent of weight loss with surgery or on which participants maintained the lower weight, Dr. Edge noted; “However, overall, most people who have weight reduction surgery have major weight loss.”

At this point, he said, “we can now tell women with obesity that in addition to the many other advantages of weight loss, their risk of getting breast cancer will also be reduced.”

The study was supported by the Ontario Bariatric Registry and ICES, which is funded by an annual grant from the Ontario Ministry of Health and the Ontario Ministry of Long-Term Care. Dr. Doumouras, Dr. Dimick, Dr. Pilewskie, and Dr. Edge reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Bariatric surgery for obesity is associated with a reduced risk of developing breast cancer, new data suggest.

In a matched cohort study of more than 69,000 Canadian women, risk for incident breast cancer at 1 year was 40% higher among women who had not undergone bariatric surgery, compared with those who had. The risk remained elevated through 5 years of follow-up.

The findings were “definitely a bit surprising,” study author Aristithes G. Doumouras, MD, MPH, assistant professor of surgery at McMaster University, Hamilton, Ont., said in an interview. “The patients that underwent bariatric surgery had better cancer outcomes than patients who weighed less than they did, so it showed that there was more at play than just weight loss. This effect was durable [and] shows how powerful the surgery is, [as well as] the fact that we haven’t even explored all of its effects.”

The study was published online in JAMA Surgery.
 

Protective association

To determine whether there is a residual risk for breast cancer following bariatric surgery for obesity, the investigators analyzed clinical and administrative data collected between 2010 and 2016 in Ontario. They retrospectively matched women with obesity who underwent bariatric surgery with women without a history of bariatric surgery. Participants were matched by age and breast cancer screening status. Covariates included diabetes status, neighborhood income quintile, and measures of health care use. The population included 69,260 women (mean age, 45 years).

Among participants who underwent bariatric surgery for obesity, baseline body mass index was greater than 35 for those with related comorbid conditions, and BMI was greater than 40 for those without comorbid conditions. The investigators categorized nonsurgical control patients in accordance with the following four BMI categories: less than 25, 25-29, 30-34, and greater than or equal to 35. Each control group, as well as the surgical group, included 13,852 women.

Participants in the surgical group were followed for 5 years after bariatric surgery. Those in the nonsurgical group were followed for 5 years after the index date (that is, the date of BMI measurement).

In the overall population, 659 cases of breast cancer were diagnosed in the overall population (0.95%) during the study period. This total included 103 (0.74%) cancers in the surgical cohort; 128 (0.92%) in the group with BMI less than 25; 143 (1.03%) among those with BMI 25-29; 150 (1.08%) in the group with BMI 30-34; and 135 (0.97%) among those with BMI greater than or equal to 35.

Most cancers were stage I. There were 65 cases among those with BMI less than 25; 76 for those with BMI of 25-29; 65 for BMI of 30-34; 67 for BMI greater than or equal to 35, and 60 for the surgery group.

Most tumors were of medium grade and were estrogen receptor positive, progesterone receptor positive, and ERBB2 negative. No significant differences were observed across the groups for stage, grade, or hormone status.

There was an increased hazard for incident breast cancer in the nonsurgical group, compared with the postsurgical group after washout periods of 1 year (hazard ratio, 1.40), 2 years (HR, 1.31), and 5 years (HR, 1.38).

In a comparison of the postsurgical cohort with the nonsurgical cohort with BMI less than 25, the hazard of incident breast cancer was not significantly different for any of the washout periods, but there was a reduced hazard for incident breast cancer among postsurgical patients than among nonsurgical patients in all high BMI categories (BMI ≥ 25).

“Taken together, these results demonstrate that the protective association between substantial weight loss via bariatric surgery and breast cancer risk is sustained after 5 years following surgery and that it is associated with a baseline risk similar to that of women with BMI less than 25,” the investigators write.

Nevertheless, Dr. Doumouras said “the interaction between the surgery and individuals is poorly studied, and this level of personalized medicine is simply not there yet. We are working on developing a prospective cohort that has genetic, protein, and microbiome [data] to help answer these questions.”

There are not enough women in subpopulations such as BRCA carriers to study at this point, he added. “This is where more patients and time will really help the research process.”
 

A universal benefit?

“Although these findings are important overall for the general population at risk for breast cancer, we raise an important caveat: The benefit of surgical weight loss may not be universal,” write Justin B. Dimick, MD, MPH, surgical innovation editor for JAMA Surgery, and Melissa L. Pilewskie, MD, both of the University of Michigan, Ann Arbor, in an accompanying commentary.

“In addition to lifestyle factors, several nonmodifiable risk factors, such as a genetic predisposition, strong family history, personal history of a high-risk breast lesion, or history of chest wall radiation, impart significant elevation in risk, and the data remain mixed on the impact of weight loss for individuals in these high-risk cohorts,” they add.

“Further study to elucidate the underlying mechanism associated with obesity, weight loss, and breast cancer risk should help guide strategies for risk reduction that are specific to unique high-risk cohorts, because modifiable risk factors may not portend the same benefit among all groups.”

Commenting on the findings, Stephen Edge, MD, breast surgeon and vice president for system quality and outcomes at Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., said, “The importance of this study is that it shows that weight loss in midlife can reduce breast cancer risk back to or even below the risk of similar people who were not obese. This has major implications for counseling women.”

The investigators did not have information on the extent of weight loss with surgery or on which participants maintained the lower weight, Dr. Edge noted; “However, overall, most people who have weight reduction surgery have major weight loss.”

At this point, he said, “we can now tell women with obesity that in addition to the many other advantages of weight loss, their risk of getting breast cancer will also be reduced.”

The study was supported by the Ontario Bariatric Registry and ICES, which is funded by an annual grant from the Ontario Ministry of Health and the Ontario Ministry of Long-Term Care. Dr. Doumouras, Dr. Dimick, Dr. Pilewskie, and Dr. Edge reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Bariatric surgery for obesity is associated with a reduced risk of developing breast cancer, new data suggest.

In a matched cohort study of more than 69,000 Canadian women, risk for incident breast cancer at 1 year was 40% higher among women who had not undergone bariatric surgery, compared with those who had. The risk remained elevated through 5 years of follow-up.

The findings were “definitely a bit surprising,” study author Aristithes G. Doumouras, MD, MPH, assistant professor of surgery at McMaster University, Hamilton, Ont., said in an interview. “The patients that underwent bariatric surgery had better cancer outcomes than patients who weighed less than they did, so it showed that there was more at play than just weight loss. This effect was durable [and] shows how powerful the surgery is, [as well as] the fact that we haven’t even explored all of its effects.”

The study was published online in JAMA Surgery.
 

Protective association

To determine whether there is a residual risk for breast cancer following bariatric surgery for obesity, the investigators analyzed clinical and administrative data collected between 2010 and 2016 in Ontario. They retrospectively matched women with obesity who underwent bariatric surgery with women without a history of bariatric surgery. Participants were matched by age and breast cancer screening status. Covariates included diabetes status, neighborhood income quintile, and measures of health care use. The population included 69,260 women (mean age, 45 years).

Among participants who underwent bariatric surgery for obesity, baseline body mass index was greater than 35 for those with related comorbid conditions, and BMI was greater than 40 for those without comorbid conditions. The investigators categorized nonsurgical control patients in accordance with the following four BMI categories: less than 25, 25-29, 30-34, and greater than or equal to 35. Each control group, as well as the surgical group, included 13,852 women.

Participants in the surgical group were followed for 5 years after bariatric surgery. Those in the nonsurgical group were followed for 5 years after the index date (that is, the date of BMI measurement).

In the overall population, 659 cases of breast cancer were diagnosed in the overall population (0.95%) during the study period. This total included 103 (0.74%) cancers in the surgical cohort; 128 (0.92%) in the group with BMI less than 25; 143 (1.03%) among those with BMI 25-29; 150 (1.08%) in the group with BMI 30-34; and 135 (0.97%) among those with BMI greater than or equal to 35.

Most cancers were stage I. There were 65 cases among those with BMI less than 25; 76 for those with BMI of 25-29; 65 for BMI of 30-34; 67 for BMI greater than or equal to 35, and 60 for the surgery group.

Most tumors were of medium grade and were estrogen receptor positive, progesterone receptor positive, and ERBB2 negative. No significant differences were observed across the groups for stage, grade, or hormone status.

There was an increased hazard for incident breast cancer in the nonsurgical group, compared with the postsurgical group after washout periods of 1 year (hazard ratio, 1.40), 2 years (HR, 1.31), and 5 years (HR, 1.38).

In a comparison of the postsurgical cohort with the nonsurgical cohort with BMI less than 25, the hazard of incident breast cancer was not significantly different for any of the washout periods, but there was a reduced hazard for incident breast cancer among postsurgical patients than among nonsurgical patients in all high BMI categories (BMI ≥ 25).

“Taken together, these results demonstrate that the protective association between substantial weight loss via bariatric surgery and breast cancer risk is sustained after 5 years following surgery and that it is associated with a baseline risk similar to that of women with BMI less than 25,” the investigators write.

Nevertheless, Dr. Doumouras said “the interaction between the surgery and individuals is poorly studied, and this level of personalized medicine is simply not there yet. We are working on developing a prospective cohort that has genetic, protein, and microbiome [data] to help answer these questions.”

There are not enough women in subpopulations such as BRCA carriers to study at this point, he added. “This is where more patients and time will really help the research process.”
 

A universal benefit?

“Although these findings are important overall for the general population at risk for breast cancer, we raise an important caveat: The benefit of surgical weight loss may not be universal,” write Justin B. Dimick, MD, MPH, surgical innovation editor for JAMA Surgery, and Melissa L. Pilewskie, MD, both of the University of Michigan, Ann Arbor, in an accompanying commentary.

“In addition to lifestyle factors, several nonmodifiable risk factors, such as a genetic predisposition, strong family history, personal history of a high-risk breast lesion, or history of chest wall radiation, impart significant elevation in risk, and the data remain mixed on the impact of weight loss for individuals in these high-risk cohorts,” they add.

“Further study to elucidate the underlying mechanism associated with obesity, weight loss, and breast cancer risk should help guide strategies for risk reduction that are specific to unique high-risk cohorts, because modifiable risk factors may not portend the same benefit among all groups.”

Commenting on the findings, Stephen Edge, MD, breast surgeon and vice president for system quality and outcomes at Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., said, “The importance of this study is that it shows that weight loss in midlife can reduce breast cancer risk back to or even below the risk of similar people who were not obese. This has major implications for counseling women.”

The investigators did not have information on the extent of weight loss with surgery or on which participants maintained the lower weight, Dr. Edge noted; “However, overall, most people who have weight reduction surgery have major weight loss.”

At this point, he said, “we can now tell women with obesity that in addition to the many other advantages of weight loss, their risk of getting breast cancer will also be reduced.”

The study was supported by the Ontario Bariatric Registry and ICES, which is funded by an annual grant from the Ontario Ministry of Health and the Ontario Ministry of Long-Term Care. Dr. Doumouras, Dr. Dimick, Dr. Pilewskie, and Dr. Edge reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.