Cutis

To improve patient care and outcomes, leading dermatologists offered their recommendations on acne scar treatments. Consideration must be given to:

• Effaclar BB Blur
  La Roche-Posay Laboratoire Dermatologique
  “Unfortunately, acne scars are permanent, but by applying cosmetics over the skin, you can minimize their appearance. Combining ingredients that give cosmetic coverage, minimize pores, and absorb oil, this product gives the skin a brighter, more even complexion.”
  — Joshua Zeichner, MD, New York, New York

• Fraxel
  Valeant Pharmaceuticals International, Inc
  Recommended by Gary Goldenberg, MD, New York, New York

• Glytone Rejuvenating Mini Peel Gel
  Pierre Fabre Dermo Cosmetique USA
  “This gel product contains a low concentration of glycolic acid. It can be applied at home, left on the skin for 10 minutes, and neutralized with water.”
  —Cherise M. Levi, DO, New York, New York

• SkinMedica Retinol Complex 0.25
  Allergan
  “Retinol will help to minimize acne scarring.”
  — Shari Lipner, MD, PhD, New York, New York

Cutis invites readers to send us their recommendations. Cleansing devices and self-tanners will be featured in upcoming editions of Cosmetic Corner. Please e-mail your recommendation(s) to the Editorial Office.

Disclaimer: Opinions expressed herein do not necessarily reflect those of Cutis or Frontline Medical Communications Inc. and shall not be used for product endorsement purposes. Any reference made to a specific commercial product does not indicate or imply that Cutis or Frontline Medical Communications Inc. endorses, recommends, or favors the product mentioned. No guarantee is given to the effects of recommended products.

To improve patient care and outcomes, leading dermatologists offered their recommendations on acne scar treatments. Consideration must be given to:

• Effaclar BB Blur
  La Roche-Posay Laboratoire Dermatologique
  “Unfortunately, acne scars are permanent, but by applying cosmetics over the skin, you can minimize their appearance. Combining ingredients that give cosmetic coverage, minimize pores, and absorb oil, this product gives the skin a brighter, more even complexion.”
  — Joshua Zeichner, MD, New York, New York

• Fraxel
  Valeant Pharmaceuticals International, Inc
  Recommended by Gary Goldenberg, MD, New York, New York

• Glytone Rejuvenating Mini Peel Gel
  Pierre Fabre Dermo Cosmetique USA
  “This gel product contains a low concentration of glycolic acid. It can be applied at home, left on the skin for 10 minutes, and neutralized with water.”
  —Cherise M. Levi, DO, New York, New York

• SkinMedica Retinol Complex 0.25
  Allergan
  “Retinol will help to minimize acne scarring.”
  — Shari Lipner, MD, PhD, New York, New York

Cutis invites readers to send us their recommendations. Cleansing devices and self-tanners will be featured in upcoming editions of Cosmetic Corner. Please e-mail your recommendation(s) to the Editorial Office.

Disclaimer: Opinions expressed herein do not necessarily reflect those of Cutis or Frontline Medical Communications Inc. and shall not be used for product endorsement purposes. Any reference made to a specific commercial product does not indicate or imply that Cutis or Frontline Medical Communications Inc. endorses, recommends, or favors the product mentioned. No guarantee is given to the effects of recommended products.

To improve patient care and outcomes, leading dermatologists offered their recommendations on acne scar treatments. Consideration must be given to:

• Effaclar BB Blur
  La Roche-Posay Laboratoire Dermatologique
  “Unfortunately, acne scars are permanent, but by applying cosmetics over the skin, you can minimize their appearance. Combining ingredients that give cosmetic coverage, minimize pores, and absorb oil, this product gives the skin a brighter, more even complexion.”
  — Joshua Zeichner, MD, New York, New York

• Fraxel
  Valeant Pharmaceuticals International, Inc
  Recommended by Gary Goldenberg, MD, New York, New York

• Glytone Rejuvenating Mini Peel Gel
  Pierre Fabre Dermo Cosmetique USA
  “This gel product contains a low concentration of glycolic acid. It can be applied at home, left on the skin for 10 minutes, and neutralized with water.”
  —Cherise M. Levi, DO, New York, New York

• SkinMedica Retinol Complex 0.25
  Allergan
  “Retinol will help to minimize acne scarring.”
  — Shari Lipner, MD, PhD, New York, New York

Cutis invites readers to send us their recommendations. Cleansing devices and self-tanners will be featured in upcoming editions of Cosmetic Corner. Please e-mail your recommendation(s) to the Editorial Office.

Disclaimer: Opinions expressed herein do not necessarily reflect those of Cutis or Frontline Medical Communications Inc. and shall not be used for product endorsement purposes. Any reference made to a specific commercial product does not indicate or imply that Cutis or Frontline Medical Communications Inc. endorses, recommends, or favors the product mentioned. No guarantee is given to the effects of recommended products.

CD30⁺ primary cutaneous lymphoproliferative disorders (pcLPDs) are the second most common cause of cutaneous T-cell lymphoma, accounting for approximately 25% to 30% of cases.¹ These disorders comprise a spectrum that includes primary cutaneous anaplastic large-cell lymphoma (pcALCL); lymphomatoid papulosis (LyP); and borderline lesions, which share clinicopathologic features of both pcALCL and LyP. Lymphomatoid papulosis is characterized as chronic, recurrent, papular or papulonodular skin lesions that typically are multifocal and regress spontaneously within weeks to months, only leaving small scars with atrophy and/or hyperpigmentation.² Cutaneous anaplastic large-cell lymphoma typically presents as solitary or grouped nodules or tumors that may undergo spontaneous partial or complete regression in approximately 25% of cases³ but often persist if not treated. Patients may have an array of lesions comprising the spectrum of CD30 pcLPDs.⁴

There is no curative therapy for CD30⁺ pcLPDs. Although active treatment is not necessary for LyP, low-dose methotrexate (MTX)(10–50 mg weekly) or phototherapy are the preferred initial suppressive therapies for symptomatic patients with scarring, facial lesions, or multiple symptomatic lesions.⁵ Observation with expectant follow-up is an option in pcALCL, though spontaneous regression is less likely than in LyP. For single or grouped pcALCL lesions, local radiation is the first-line therapy.⁶ Multifocal pcALCL lesions also can be treated with low-dose MTX,^2,5 as in LyP, or local radiation to selected areas. Although local radiotherapy is considered a first-line treatment in pcALCL, there is limited evidence on its clinical efficacy as well as the optimal dose and technique. We report the complete response of refractory pcALCL lesions to low-dose radiation while remaining on MTX weekly without any adverse effects.

Case Report

A 51-year-old woman presented with a 3-year history of CD30⁺ pcLPD manifesting primarily as pcALCL involving the head and neck, as well as LyP involving the head, arms, and trunk (T3N0M0). For 2 years her treatment regimen included clobetasol propionate cream 0.05% as needed for new lesions and 2 courses of standard-dose localized external beam radiation for larger pcALCL tumors on the right cheek and right side of the chin (Figure 1)(total dose for each course of treatment was 20 Gy and 36 Gy, respectively, each administered over 2–3 weeks). Because new unsightly papulonodules continued to develop on the patient’s face, she subsequently required low-dose oral MTX 30 mg once weekly for suppression of new lesions and was stable on this regimen for a year. However, she experienced an increase in LyP/pcALCL activity on the face during a 2-week break from MTX when she developed a herpes zoster infection on the right side of the forehead.

On physical examination 1 month later, 5 tiny pink papules scattered on the left eyebrow, left cheek, and left side of the chin were noted. She was advised to continue applying the clobetasol cream as needed and was restarted on MTX 10 mg once weekly. However, she developed 2 additional 1-cm nodules on the left side of the chin, neck, and shoulder. Methotrexate was increased to 30 mg once weekly over 2 weeks, which was the original dose prior to interruption, but the nodules grew to 1.5-cm in diameter. Due to their clinical appearance, the nodules were believed to be early pcALCL lesions (Figure 2A). Given the cosmetically sensitive location of the nodules, palliative radiotherapy was recommended rather than observe for possible regression. Based on a prior report by Neelis et al⁷ demonstrating efficacy of low-dose radiotherapy for cutaneous T-cell lymphoma and cutaneous B-cell lymphoma, we recommended starting with low radiation doses. Our patient was treated with 400 cGy twice to the left side of the chin and left side of the neck (800 cGy total at each site) while remaining on MTX 30 mg once weekly. This treatment was well tolerated without side effects and no evidence of radiation dermatitis. On follow-up examination 1 week later, the nodules had regressed and no new lesions were present (Figure 2B).

The patient has stayed on oral MTX and occasionally develops small lesions that quickly resolve with clobetasol cream. She has been followed for 3 years after radiotherapy and all 3 previously irradiated sites have remained recurrence free. Furthermore, she has not developed any new larger nodules or tumors and her MTX dose has been decreased to 15 mg once weekly.

Comment

Local radiotherapy is considered a first-line treatment of pcALCL; however, there is limited evidence on its clinical efficacy as well as the optimal dose and technique. Although no standard dose exists for pcALCL, the National Comprehensive Cancer Network guidelines⁸ recommend doses of 12 to 36 Gy in mycosis fungoides/Sézary syndrome subtypes of cutaneous T-cell lymphoma, which are consistent with guidelines published by the European Society for Medical Oncology.⁹ High complete response rates have been demonstrated in pcALCL at doses of 34 to 44 Gy⁶; however, lesions tend to recur elsewhere on the skin in 36% to 41% of patients despite treatment.^2,10 Lower doses of radiation therapy would provide several advantages over higher-dose therapy if a complete response could be achieved without greatly increasing the local recurrence rate. In cases of local recurrence, low-dose radiation would more easily permit retreatment of lesions compared to higher doses of radiation. Similarly, in patients with multifocal pcALCL, lower doses of radiotherapy may allow for treatment of larger skin areas while limiting potential treatment risks. Furthermore, low-dose therapy would allow for treatments to be delivered more quickly and with less inconvenience to the patient who is likely to need multiple future treatments to other areas. Low-dose radiation has been described with a favorable efficacy profile for mycosis fungoides^7,11 but has not been studied in patients with CD30⁺ pcLPDs.

Our case is notable because the patient remained on MTX during radiation therapy. Because MTX can act as a radiosensitizer, current standard practice is to stop MTX while administering radiation therapy. High oncologic doses of MTX can occasionally produce severe skin reactions at the irradiated site^12-14; however, reports of the use of lower weekly doses in combination with radiation are sparse. Our patient had refractory disfiguring facial lesions that would immediately recur once MTX was stopped. Low-dose radiation therapy was administered while she remained on her weekly MTX doses. With this treatment, she achieved a complete response, developed no radiation dermatitis, and had no further new skin lesions appear.

Conclusion

We reported the use of low-dose radiation therapy for the treatment of localized pcALCL in a patient who remained on low-dose oral MTX. Additional studies will be necessary to more fully evaluate the efficacy of using low-dose radiation both as monotherapy and in combination with MTX for pcALCL.

CD30⁺ primary cutaneous lymphoproliferative disorders (pcLPDs) are the second most common cause of cutaneous T-cell lymphoma, accounting for approximately 25% to 30% of cases.¹ These disorders comprise a spectrum that includes primary cutaneous anaplastic large-cell lymphoma (pcALCL); lymphomatoid papulosis (LyP); and borderline lesions, which share clinicopathologic features of both pcALCL and LyP. Lymphomatoid papulosis is characterized as chronic, recurrent, papular or papulonodular skin lesions that typically are multifocal and regress spontaneously within weeks to months, only leaving small scars with atrophy and/or hyperpigmentation.² Cutaneous anaplastic large-cell lymphoma typically presents as solitary or grouped nodules or tumors that may undergo spontaneous partial or complete regression in approximately 25% of cases³ but often persist if not treated. Patients may have an array of lesions comprising the spectrum of CD30 pcLPDs.⁴

There is no curative therapy for CD30⁺ pcLPDs. Although active treatment is not necessary for LyP, low-dose methotrexate (MTX)(10–50 mg weekly) or phototherapy are the preferred initial suppressive therapies for symptomatic patients with scarring, facial lesions, or multiple symptomatic lesions.⁵ Observation with expectant follow-up is an option in pcALCL, though spontaneous regression is less likely than in LyP. For single or grouped pcALCL lesions, local radiation is the first-line therapy.⁶ Multifocal pcALCL lesions also can be treated with low-dose MTX,^2,5 as in LyP, or local radiation to selected areas. Although local radiotherapy is considered a first-line treatment in pcALCL, there is limited evidence on its clinical efficacy as well as the optimal dose and technique. We report the complete response of refractory pcALCL lesions to low-dose radiation while remaining on MTX weekly without any adverse effects.

Case Report

A 51-year-old woman presented with a 3-year history of CD30⁺ pcLPD manifesting primarily as pcALCL involving the head and neck, as well as LyP involving the head, arms, and trunk (T3N0M0). For 2 years her treatment regimen included clobetasol propionate cream 0.05% as needed for new lesions and 2 courses of standard-dose localized external beam radiation for larger pcALCL tumors on the right cheek and right side of the chin (Figure 1)(total dose for each course of treatment was 20 Gy and 36 Gy, respectively, each administered over 2–3 weeks). Because new unsightly papulonodules continued to develop on the patient’s face, she subsequently required low-dose oral MTX 30 mg once weekly for suppression of new lesions and was stable on this regimen for a year. However, she experienced an increase in LyP/pcALCL activity on the face during a 2-week break from MTX when she developed a herpes zoster infection on the right side of the forehead.

On physical examination 1 month later, 5 tiny pink papules scattered on the left eyebrow, left cheek, and left side of the chin were noted. She was advised to continue applying the clobetasol cream as needed and was restarted on MTX 10 mg once weekly. However, she developed 2 additional 1-cm nodules on the left side of the chin, neck, and shoulder. Methotrexate was increased to 30 mg once weekly over 2 weeks, which was the original dose prior to interruption, but the nodules grew to 1.5-cm in diameter. Due to their clinical appearance, the nodules were believed to be early pcALCL lesions (Figure 2A). Given the cosmetically sensitive location of the nodules, palliative radiotherapy was recommended rather than observe for possible regression. Based on a prior report by Neelis et al⁷ demonstrating efficacy of low-dose radiotherapy for cutaneous T-cell lymphoma and cutaneous B-cell lymphoma, we recommended starting with low radiation doses. Our patient was treated with 400 cGy twice to the left side of the chin and left side of the neck (800 cGy total at each site) while remaining on MTX 30 mg once weekly. This treatment was well tolerated without side effects and no evidence of radiation dermatitis. On follow-up examination 1 week later, the nodules had regressed and no new lesions were present (Figure 2B).

The patient has stayed on oral MTX and occasionally develops small lesions that quickly resolve with clobetasol cream. She has been followed for 3 years after radiotherapy and all 3 previously irradiated sites have remained recurrence free. Furthermore, she has not developed any new larger nodules or tumors and her MTX dose has been decreased to 15 mg once weekly.

Comment

Local radiotherapy is considered a first-line treatment of pcALCL; however, there is limited evidence on its clinical efficacy as well as the optimal dose and technique. Although no standard dose exists for pcALCL, the National Comprehensive Cancer Network guidelines⁸ recommend doses of 12 to 36 Gy in mycosis fungoides/Sézary syndrome subtypes of cutaneous T-cell lymphoma, which are consistent with guidelines published by the European Society for Medical Oncology.⁹ High complete response rates have been demonstrated in pcALCL at doses of 34 to 44 Gy⁶; however, lesions tend to recur elsewhere on the skin in 36% to 41% of patients despite treatment.^2,10 Lower doses of radiation therapy would provide several advantages over higher-dose therapy if a complete response could be achieved without greatly increasing the local recurrence rate. In cases of local recurrence, low-dose radiation would more easily permit retreatment of lesions compared to higher doses of radiation. Similarly, in patients with multifocal pcALCL, lower doses of radiotherapy may allow for treatment of larger skin areas while limiting potential treatment risks. Furthermore, low-dose therapy would allow for treatments to be delivered more quickly and with less inconvenience to the patient who is likely to need multiple future treatments to other areas. Low-dose radiation has been described with a favorable efficacy profile for mycosis fungoides^7,11 but has not been studied in patients with CD30⁺ pcLPDs.

Our case is notable because the patient remained on MTX during radiation therapy. Because MTX can act as a radiosensitizer, current standard practice is to stop MTX while administering radiation therapy. High oncologic doses of MTX can occasionally produce severe skin reactions at the irradiated site^12-14; however, reports of the use of lower weekly doses in combination with radiation are sparse. Our patient had refractory disfiguring facial lesions that would immediately recur once MTX was stopped. Low-dose radiation therapy was administered while she remained on her weekly MTX doses. With this treatment, she achieved a complete response, developed no radiation dermatitis, and had no further new skin lesions appear.

Conclusion

We reported the use of low-dose radiation therapy for the treatment of localized pcALCL in a patient who remained on low-dose oral MTX. Additional studies will be necessary to more fully evaluate the efficacy of using low-dose radiation both as monotherapy and in combination with MTX for pcALCL.

CD30⁺ primary cutaneous lymphoproliferative disorders (pcLPDs) are the second most common cause of cutaneous T-cell lymphoma, accounting for approximately 25% to 30% of cases.¹ These disorders comprise a spectrum that includes primary cutaneous anaplastic large-cell lymphoma (pcALCL); lymphomatoid papulosis (LyP); and borderline lesions, which share clinicopathologic features of both pcALCL and LyP. Lymphomatoid papulosis is characterized as chronic, recurrent, papular or papulonodular skin lesions that typically are multifocal and regress spontaneously within weeks to months, only leaving small scars with atrophy and/or hyperpigmentation.² Cutaneous anaplastic large-cell lymphoma typically presents as solitary or grouped nodules or tumors that may undergo spontaneous partial or complete regression in approximately 25% of cases³ but often persist if not treated. Patients may have an array of lesions comprising the spectrum of CD30 pcLPDs.⁴

There is no curative therapy for CD30⁺ pcLPDs. Although active treatment is not necessary for LyP, low-dose methotrexate (MTX)(10–50 mg weekly) or phototherapy are the preferred initial suppressive therapies for symptomatic patients with scarring, facial lesions, or multiple symptomatic lesions.⁵ Observation with expectant follow-up is an option in pcALCL, though spontaneous regression is less likely than in LyP. For single or grouped pcALCL lesions, local radiation is the first-line therapy.⁶ Multifocal pcALCL lesions also can be treated with low-dose MTX,^2,5 as in LyP, or local radiation to selected areas. Although local radiotherapy is considered a first-line treatment in pcALCL, there is limited evidence on its clinical efficacy as well as the optimal dose and technique. We report the complete response of refractory pcALCL lesions to low-dose radiation while remaining on MTX weekly without any adverse effects.

Case Report

A 51-year-old woman presented with a 3-year history of CD30⁺ pcLPD manifesting primarily as pcALCL involving the head and neck, as well as LyP involving the head, arms, and trunk (T3N0M0). For 2 years her treatment regimen included clobetasol propionate cream 0.05% as needed for new lesions and 2 courses of standard-dose localized external beam radiation for larger pcALCL tumors on the right cheek and right side of the chin (Figure 1)(total dose for each course of treatment was 20 Gy and 36 Gy, respectively, each administered over 2–3 weeks). Because new unsightly papulonodules continued to develop on the patient’s face, she subsequently required low-dose oral MTX 30 mg once weekly for suppression of new lesions and was stable on this regimen for a year. However, she experienced an increase in LyP/pcALCL activity on the face during a 2-week break from MTX when she developed a herpes zoster infection on the right side of the forehead.

On physical examination 1 month later, 5 tiny pink papules scattered on the left eyebrow, left cheek, and left side of the chin were noted. She was advised to continue applying the clobetasol cream as needed and was restarted on MTX 10 mg once weekly. However, she developed 2 additional 1-cm nodules on the left side of the chin, neck, and shoulder. Methotrexate was increased to 30 mg once weekly over 2 weeks, which was the original dose prior to interruption, but the nodules grew to 1.5-cm in diameter. Due to their clinical appearance, the nodules were believed to be early pcALCL lesions (Figure 2A). Given the cosmetically sensitive location of the nodules, palliative radiotherapy was recommended rather than observe for possible regression. Based on a prior report by Neelis et al⁷ demonstrating efficacy of low-dose radiotherapy for cutaneous T-cell lymphoma and cutaneous B-cell lymphoma, we recommended starting with low radiation doses. Our patient was treated with 400 cGy twice to the left side of the chin and left side of the neck (800 cGy total at each site) while remaining on MTX 30 mg once weekly. This treatment was well tolerated without side effects and no evidence of radiation dermatitis. On follow-up examination 1 week later, the nodules had regressed and no new lesions were present (Figure 2B).

The patient has stayed on oral MTX and occasionally develops small lesions that quickly resolve with clobetasol cream. She has been followed for 3 years after radiotherapy and all 3 previously irradiated sites have remained recurrence free. Furthermore, she has not developed any new larger nodules or tumors and her MTX dose has been decreased to 15 mg once weekly.

Comment

Local radiotherapy is considered a first-line treatment of pcALCL; however, there is limited evidence on its clinical efficacy as well as the optimal dose and technique. Although no standard dose exists for pcALCL, the National Comprehensive Cancer Network guidelines⁸ recommend doses of 12 to 36 Gy in mycosis fungoides/Sézary syndrome subtypes of cutaneous T-cell lymphoma, which are consistent with guidelines published by the European Society for Medical Oncology.⁹ High complete response rates have been demonstrated in pcALCL at doses of 34 to 44 Gy⁶; however, lesions tend to recur elsewhere on the skin in 36% to 41% of patients despite treatment.^2,10 Lower doses of radiation therapy would provide several advantages over higher-dose therapy if a complete response could be achieved without greatly increasing the local recurrence rate. In cases of local recurrence, low-dose radiation would more easily permit retreatment of lesions compared to higher doses of radiation. Similarly, in patients with multifocal pcALCL, lower doses of radiotherapy may allow for treatment of larger skin areas while limiting potential treatment risks. Furthermore, low-dose therapy would allow for treatments to be delivered more quickly and with less inconvenience to the patient who is likely to need multiple future treatments to other areas. Low-dose radiation has been described with a favorable efficacy profile for mycosis fungoides^7,11 but has not been studied in patients with CD30⁺ pcLPDs.

Our case is notable because the patient remained on MTX during radiation therapy. Because MTX can act as a radiosensitizer, current standard practice is to stop MTX while administering radiation therapy. High oncologic doses of MTX can occasionally produce severe skin reactions at the irradiated site^12-14; however, reports of the use of lower weekly doses in combination with radiation are sparse. Our patient had refractory disfiguring facial lesions that would immediately recur once MTX was stopped. Low-dose radiation therapy was administered while she remained on her weekly MTX doses. With this treatment, she achieved a complete response, developed no radiation dermatitis, and had no further new skin lesions appear.

Conclusion

We reported the use of low-dose radiation therapy for the treatment of localized pcALCL in a patient who remained on low-dose oral MTX. Additional studies will be necessary to more fully evaluate the efficacy of using low-dose radiation both as monotherapy and in combination with MTX for pcALCL.

The Nuremberg Code in 1947,¹ the Declaration of Helsinki in 1964,² and the Belmont Report in 1979³ were cornerstones in the establishment of ethical principles in the medical field. These documents specifically highlight the concept of informed consent, which maintains that to practice ethical medicine, physicians must fully inform patients of all therapeutic benefits and especially risks as well as treatment alternatives before they consent to therapeutic intervention. Educating patients about risks of treatment is obligatory. Risk communication involves a mutual exchange of information between physicians and patients; the physician presents risk information in an understandable manner that adequately conveys pertinent data that is critical for the patient to make an informed therapeutic decision.⁴

An inherent problem with risk education is that patients may be terrified about risks associated with treatment. Some patients will refuse needed treatment because of fear.⁵ When patients have concerns about the safety profile of a treatment regimen and potential adverse effects, they may be less compliant with treatment.⁶ The intelligent noncompliance phenomenon occurs when a patient knowingly makes the choice to not adhere to treatment, and concern regarding treatment risks relative to benefits is a common reason underlying this phenomenon.^7,8

Behavioral economists have studied how individuals weigh risks. Kahneman and Tversky’s⁹ prospect theory asserts that individuals tend to overweigh unlikely risks and underweigh more certain risks, which they call the certainty effect; it is the basis of the human tendency to avoid risks in situations of likely gain and to pursue risks in situations of likely loss. The tendency to overweigh rare risks is even more pronounced for affect-rich events such as serious side effects.¹⁰ The way data are presented can affect how patients interpret the information. Context and framing of data affect patients’ perceptions.¹¹ We describe several ways to present safety data using graphical presentation of psoriasis treatment safety data as an example and explain how each one can affect patients’ perception of treatment risks.

Approaches to Presenting Safety Data

There are numerous ways to present safety data to patients, including verbal, numeric, and visual strategies.¹² Many methods of presentation are a combination of these strategies. Graphs are visual strategies to further categorize and present numeric data, and physicians may choose to incorporate these aids when presenting safety information to patients. Graphical presentations give the patient a mental picture of the data. Numerous types of graphs can be constructed. Kalb et al¹³ determined the effect of psoriasis treatment on the risk of serious infection from the Psoriasis Longitudinal Assessment and Registry (PSOLAR). We used the results from this study to demonstrate multiple ways of presenting safety data (Figures 1–3).

A graphical presentation with a truncated y-axis is a common approach (Figure 1). Graphs with truncated axes are sometimes used to conserve space or to accentuate certain differences in the graph that would otherwise be less obvious without the zoomed in y-axis.¹⁴ These graphs present quantitatively accurate information that can be visually misleading at the same time. Truncated axes accentuate differences, creating mental impressions that are not reflective of the magnitude of the numeric differences. Alternatively, a graph with a full y-axis includes both the maximum and minimum data values on the y-axis (Figure 2). The y-axis also extends maximally to the total number of patients or patient-years studied. This type of graph presents all of the numeric data without distortion.

Focus on the Patients Who Do Not Have Adverse Effects of Treatments

Fear of adverse effects is one of the most commonly reported causes of poor treatment adherence.¹⁵ New therapies for psoriasis are highly effective and safe, but as with all treatments, they also are associated with some risks. Patients may latch onto those risks too tightly or perhaps, in other circumstances, not tightly enough. The method used by a physician to present safety data to a patient may determine the patient’s perception about treatments.

When trying to give patients an accurate impression of treatment risks, it may be helpful to avoid approaches that focus on presenting the (few) cases of severe adverse drug effects since patients (and physicians) are likely to overweigh the unlikely risk of having an adverse effect if presented with this information. It may be more reassuring to focus on presenting information about the chance of not having an adverse drug effect, assuming the physician’s goal is to be reassuring.

Poor communication with patients when presenting safety data can foster exaggerated fears of an unlikely consequence to the point that patients can be left undertreated and sustaining disease symptoms.¹⁶ Physicians may strive to do no harm to their patients, but without careful presentation of safety data in the process of helping the patient make an informed decision, it is possible to do mental harm to patients in the form of fear or even, in the case of nonadherence or treatment refusal, physical harm in the form of continued disease symptoms.

One limitation of this review is that we only used graphical presentation of data as an example. Similar concerns apply to numerical data presentation. Telling a patient the risk of a severe adverse reaction is doubled by a certain treatment may be terrifying, though if the baseline risk is rare, doubling the baseline risk may represent only a minimal increase in the absolute risk. Telling a patient the risk is only 1 in 1000 may still be alarming because many patients tend to focus on the 1, but telling a patient that 999 of 1000 patients do not have a problem can be much more reassuring.

The physician’s goal—to help patients make informed decisions about their treatment—calls for him/her to assimilate safety data into useful information that the patient can use to make an informed decision.¹⁷ Overly comforting or alarming, confusing, and inaccurate information can misguide the patient, violating the ethical principle of nonmaleficence. Although there is an obligation to educate patients about risks, there may not be a purely objective way to do it. When physicians present objective data to patients, whether in numerical or graphical form, there will be an unavoidable subjective interpretation of the data. The form of presentation will have a critical effect on patients’ subjective perceptions. Physicians can present objective data in such a way as to be reassuring or frightening.

Conclusion

Despite physicians’ best-intentioned efforts, it may be impossible to avoid presenting safety data in a way that will be subjectively interpreted by patients. Physicians have a choice in how they present data to patients; their best judgment should be used in how they present data to inform patients, guide them, and offer them the best treatment outcomes.

Acknowledgment

We thank Scott Jaros, BA (Winston-Salem, North Carolina), for his assistance in the revision of the manuscript.

The Nuremberg Code in 1947,¹ the Declaration of Helsinki in 1964,² and the Belmont Report in 1979³ were cornerstones in the establishment of ethical principles in the medical field. These documents specifically highlight the concept of informed consent, which maintains that to practice ethical medicine, physicians must fully inform patients of all therapeutic benefits and especially risks as well as treatment alternatives before they consent to therapeutic intervention. Educating patients about risks of treatment is obligatory. Risk communication involves a mutual exchange of information between physicians and patients; the physician presents risk information in an understandable manner that adequately conveys pertinent data that is critical for the patient to make an informed therapeutic decision.⁴

An inherent problem with risk education is that patients may be terrified about risks associated with treatment. Some patients will refuse needed treatment because of fear.⁵ When patients have concerns about the safety profile of a treatment regimen and potential adverse effects, they may be less compliant with treatment.⁶ The intelligent noncompliance phenomenon occurs when a patient knowingly makes the choice to not adhere to treatment, and concern regarding treatment risks relative to benefits is a common reason underlying this phenomenon.^7,8

Behavioral economists have studied how individuals weigh risks. Kahneman and Tversky’s⁹ prospect theory asserts that individuals tend to overweigh unlikely risks and underweigh more certain risks, which they call the certainty effect; it is the basis of the human tendency to avoid risks in situations of likely gain and to pursue risks in situations of likely loss. The tendency to overweigh rare risks is even more pronounced for affect-rich events such as serious side effects.¹⁰ The way data are presented can affect how patients interpret the information. Context and framing of data affect patients’ perceptions.¹¹ We describe several ways to present safety data using graphical presentation of psoriasis treatment safety data as an example and explain how each one can affect patients’ perception of treatment risks.

Approaches to Presenting Safety Data

There are numerous ways to present safety data to patients, including verbal, numeric, and visual strategies.¹² Many methods of presentation are a combination of these strategies. Graphs are visual strategies to further categorize and present numeric data, and physicians may choose to incorporate these aids when presenting safety information to patients. Graphical presentations give the patient a mental picture of the data. Numerous types of graphs can be constructed. Kalb et al¹³ determined the effect of psoriasis treatment on the risk of serious infection from the Psoriasis Longitudinal Assessment and Registry (PSOLAR). We used the results from this study to demonstrate multiple ways of presenting safety data (Figures 1–3).

A graphical presentation with a truncated y-axis is a common approach (Figure 1). Graphs with truncated axes are sometimes used to conserve space or to accentuate certain differences in the graph that would otherwise be less obvious without the zoomed in y-axis.¹⁴ These graphs present quantitatively accurate information that can be visually misleading at the same time. Truncated axes accentuate differences, creating mental impressions that are not reflective of the magnitude of the numeric differences. Alternatively, a graph with a full y-axis includes both the maximum and minimum data values on the y-axis (Figure 2). The y-axis also extends maximally to the total number of patients or patient-years studied. This type of graph presents all of the numeric data without distortion.

Focus on the Patients Who Do Not Have Adverse Effects of Treatments

Fear of adverse effects is one of the most commonly reported causes of poor treatment adherence.¹⁵ New therapies for psoriasis are highly effective and safe, but as with all treatments, they also are associated with some risks. Patients may latch onto those risks too tightly or perhaps, in other circumstances, not tightly enough. The method used by a physician to present safety data to a patient may determine the patient’s perception about treatments.

When trying to give patients an accurate impression of treatment risks, it may be helpful to avoid approaches that focus on presenting the (few) cases of severe adverse drug effects since patients (and physicians) are likely to overweigh the unlikely risk of having an adverse effect if presented with this information. It may be more reassuring to focus on presenting information about the chance of not having an adverse drug effect, assuming the physician’s goal is to be reassuring.

Poor communication with patients when presenting safety data can foster exaggerated fears of an unlikely consequence to the point that patients can be left undertreated and sustaining disease symptoms.¹⁶ Physicians may strive to do no harm to their patients, but without careful presentation of safety data in the process of helping the patient make an informed decision, it is possible to do mental harm to patients in the form of fear or even, in the case of nonadherence or treatment refusal, physical harm in the form of continued disease symptoms.

One limitation of this review is that we only used graphical presentation of data as an example. Similar concerns apply to numerical data presentation. Telling a patient the risk of a severe adverse reaction is doubled by a certain treatment may be terrifying, though if the baseline risk is rare, doubling the baseline risk may represent only a minimal increase in the absolute risk. Telling a patient the risk is only 1 in 1000 may still be alarming because many patients tend to focus on the 1, but telling a patient that 999 of 1000 patients do not have a problem can be much more reassuring.

The physician’s goal—to help patients make informed decisions about their treatment—calls for him/her to assimilate safety data into useful information that the patient can use to make an informed decision.¹⁷ Overly comforting or alarming, confusing, and inaccurate information can misguide the patient, violating the ethical principle of nonmaleficence. Although there is an obligation to educate patients about risks, there may not be a purely objective way to do it. When physicians present objective data to patients, whether in numerical or graphical form, there will be an unavoidable subjective interpretation of the data. The form of presentation will have a critical effect on patients’ subjective perceptions. Physicians can present objective data in such a way as to be reassuring or frightening.

Conclusion

Despite physicians’ best-intentioned efforts, it may be impossible to avoid presenting safety data in a way that will be subjectively interpreted by patients. Physicians have a choice in how they present data to patients; their best judgment should be used in how they present data to inform patients, guide them, and offer them the best treatment outcomes.

Acknowledgment

We thank Scott Jaros, BA (Winston-Salem, North Carolina), for his assistance in the revision of the manuscript.

The Nuremberg Code in 1947,¹ the Declaration of Helsinki in 1964,² and the Belmont Report in 1979³ were cornerstones in the establishment of ethical principles in the medical field. These documents specifically highlight the concept of informed consent, which maintains that to practice ethical medicine, physicians must fully inform patients of all therapeutic benefits and especially risks as well as treatment alternatives before they consent to therapeutic intervention. Educating patients about risks of treatment is obligatory. Risk communication involves a mutual exchange of information between physicians and patients; the physician presents risk information in an understandable manner that adequately conveys pertinent data that is critical for the patient to make an informed therapeutic decision.⁴

An inherent problem with risk education is that patients may be terrified about risks associated with treatment. Some patients will refuse needed treatment because of fear.⁵ When patients have concerns about the safety profile of a treatment regimen and potential adverse effects, they may be less compliant with treatment.⁶ The intelligent noncompliance phenomenon occurs when a patient knowingly makes the choice to not adhere to treatment, and concern regarding treatment risks relative to benefits is a common reason underlying this phenomenon.^7,8

Behavioral economists have studied how individuals weigh risks. Kahneman and Tversky’s⁹ prospect theory asserts that individuals tend to overweigh unlikely risks and underweigh more certain risks, which they call the certainty effect; it is the basis of the human tendency to avoid risks in situations of likely gain and to pursue risks in situations of likely loss. The tendency to overweigh rare risks is even more pronounced for affect-rich events such as serious side effects.¹⁰ The way data are presented can affect how patients interpret the information. Context and framing of data affect patients’ perceptions.¹¹ We describe several ways to present safety data using graphical presentation of psoriasis treatment safety data as an example and explain how each one can affect patients’ perception of treatment risks.

Approaches to Presenting Safety Data

There are numerous ways to present safety data to patients, including verbal, numeric, and visual strategies.¹² Many methods of presentation are a combination of these strategies. Graphs are visual strategies to further categorize and present numeric data, and physicians may choose to incorporate these aids when presenting safety information to patients. Graphical presentations give the patient a mental picture of the data. Numerous types of graphs can be constructed. Kalb et al¹³ determined the effect of psoriasis treatment on the risk of serious infection from the Psoriasis Longitudinal Assessment and Registry (PSOLAR). We used the results from this study to demonstrate multiple ways of presenting safety data (Figures 1–3).

A graphical presentation with a truncated y-axis is a common approach (Figure 1). Graphs with truncated axes are sometimes used to conserve space or to accentuate certain differences in the graph that would otherwise be less obvious without the zoomed in y-axis.¹⁴ These graphs present quantitatively accurate information that can be visually misleading at the same time. Truncated axes accentuate differences, creating mental impressions that are not reflective of the magnitude of the numeric differences. Alternatively, a graph with a full y-axis includes both the maximum and minimum data values on the y-axis (Figure 2). The y-axis also extends maximally to the total number of patients or patient-years studied. This type of graph presents all of the numeric data without distortion.

Focus on the Patients Who Do Not Have Adverse Effects of Treatments

Fear of adverse effects is one of the most commonly reported causes of poor treatment adherence.¹⁵ New therapies for psoriasis are highly effective and safe, but as with all treatments, they also are associated with some risks. Patients may latch onto those risks too tightly or perhaps, in other circumstances, not tightly enough. The method used by a physician to present safety data to a patient may determine the patient’s perception about treatments.

When trying to give patients an accurate impression of treatment risks, it may be helpful to avoid approaches that focus on presenting the (few) cases of severe adverse drug effects since patients (and physicians) are likely to overweigh the unlikely risk of having an adverse effect if presented with this information. It may be more reassuring to focus on presenting information about the chance of not having an adverse drug effect, assuming the physician’s goal is to be reassuring.

Poor communication with patients when presenting safety data can foster exaggerated fears of an unlikely consequence to the point that patients can be left undertreated and sustaining disease symptoms.¹⁶ Physicians may strive to do no harm to their patients, but without careful presentation of safety data in the process of helping the patient make an informed decision, it is possible to do mental harm to patients in the form of fear or even, in the case of nonadherence or treatment refusal, physical harm in the form of continued disease symptoms.

One limitation of this review is that we only used graphical presentation of data as an example. Similar concerns apply to numerical data presentation. Telling a patient the risk of a severe adverse reaction is doubled by a certain treatment may be terrifying, though if the baseline risk is rare, doubling the baseline risk may represent only a minimal increase in the absolute risk. Telling a patient the risk is only 1 in 1000 may still be alarming because many patients tend to focus on the 1, but telling a patient that 999 of 1000 patients do not have a problem can be much more reassuring.

The physician’s goal—to help patients make informed decisions about their treatment—calls for him/her to assimilate safety data into useful information that the patient can use to make an informed decision.¹⁷ Overly comforting or alarming, confusing, and inaccurate information can misguide the patient, violating the ethical principle of nonmaleficence. Although there is an obligation to educate patients about risks, there may not be a purely objective way to do it. When physicians present objective data to patients, whether in numerical or graphical form, there will be an unavoidable subjective interpretation of the data. The form of presentation will have a critical effect on patients’ subjective perceptions. Physicians can present objective data in such a way as to be reassuring or frightening.

Conclusion

Despite physicians’ best-intentioned efforts, it may be impossible to avoid presenting safety data in a way that will be subjectively interpreted by patients. Physicians have a choice in how they present data to patients; their best judgment should be used in how they present data to inform patients, guide them, and offer them the best treatment outcomes.

Acknowledgment

We thank Scott Jaros, BA (Winston-Salem, North Carolina), for his assistance in the revision of the manuscript.

Bullous pemphigoid (BP) is an acquired, autoimmune, subepidermal blistering disease that is more common in elderly patients.¹ An association with internal neoplasms and BP has been established; however, there is debate regarding the precise nature of the relationship.² Several gastrointestinal tract tumors have been associated with BP, including adenocarcinoma of the colon, adenosquamous cell carcinoma and adenocarcinoma of the stomach, adenocarcinoma of the rectum, and liver and bile duct malignancies.^3-5 Association with pancreatic neoplasms (eg, carcinoma of the pancreas) rarely has been reported.^5-7 We present an unusual case of a lymphoepithelial cyst of the pancreas in a patient with BP.

Case Report

A 67-year-old man presented with erythematous crusted plaques and pink scars over the chest, back, arms, and legs (Figure 1). A 1.5-cm tense bullous lesion was observed on the right knee. The patient’s medical history was notable for biopsy-proven BP of 8 months’ duration as well as diabetes mellitus and hypothyroidism. The patient was being followed by his surgeon for a 1.9-cm soft-tissue lesion in the pancreatic tail and was awaiting surgical excision at the time of the current presentation. The pancreatic lesion was discovered incidentally on magnetic resonance imaging performed following urologic concerns. At the current presentation, the patient’s medications included nifedipine, hydralazine, metoprolol, torsemide, aspirin, levothyroxine, atorvastatin, insulin lispro, and insulin glargine. He had previously been treated for BP with prednisone at a maximum dosage of 60 mg daily, clobetasol propionate cream 0.05%, and mupirocin ointment 2% without improvement. Because of substantial weight gain and poorly controlled diabetes, prednisone was discontinued.

Bullous pemphigoid had been diagnosed histopathologically by a prior dermatologist. Hematoxylin and eosin staining demonstrated a subepidermal separation with eosinophils within the perivascular infiltrate (Figure 2). Direct immunofluorescence was noted in a linear pattern at the dermoepidermal junction with IgG and C3. Bullous pemphigoid antigen antibodies 1 and 2 were obtained via enzyme-linked immunosorbent assay with a positive BP-1 antigen antibody of 19 U/mL (positive, >15 U/mL) and a normal BP-2 antigen antibody of less than 9 U/mL (reference range, <9 U/mL). The glucagon level was elevated at 245 pg/mL (reference range, ≤134 pg/mL).

The patient was prescribed minocycline 100 mg twice daily and niacinamide 500 mg 3 times daily. Topical treatment with clobetasol and mupirocin was continued. One month later, the patient returned with an increase in disease activity. Changes to his therapeutic regimen were deferred until after excision of the pancreatic lesion based on the decision not to start immunosuppressive therapy until the precise nature of the pancreatic lesion was determined.

The patient underwent excision of the pancreatic lesion approximately 3 months later, which proved to be a benign lymphoepithelial cyst of the pancreas. Histology of the cyst consisted of dense fibrous tissue with a squamous epithelial lining focally infiltrated by lymphocytes (Figure 3A). Immunoperoxidase staining of the cyst revealed focal linear areas of C3d staining along the basement membrane of the stratified squamous epithelium (Figure 3B).

The patient stated that his skin started to improve virtually immediately following the excision without systemic treatment for BP. On follow-up examination 3 weeks postoperatively, no bullae were observed and there was a notable decrease in erythematous crusted plaques (Figure 4).

Comment

Paraneoplastic BP has been documented; however, lymphoepithelial cysts of the pancreas in association with BP are rare. We propose that the lymphoepithelial cyst of the pancreas provided the immunologic stimulus for the development of cutaneous BP based on the observation that our patient’s condition remarkably improved with resection of the tumor.

There are fewer than 100 cases of lymphoepithelial cysts of the pancreas reported in the literature.⁸ The histologic appearance is consistent with a true cyst exhibiting a well-differentiated stratified squamous epithelium, often with keratinization, surrounded by lymphoid tissue. These tumors are most commonly seen in middle-aged men and are frequently found incidentally,^8-10 as was the case with our patient. Although histologically similar, lymphoepithelial cysts of the pancreas are considered distinct from lymphoepithelial cysts of the parotid gland or head and neck region.¹⁰ Lymphoepithelial cysts of the pancreas are unrelated to elevated glucagon levels; it is likely that our patient’s glucagon levels were associated with his history of diabetes.¹¹

In theory, any process that involves deposition of C3 should be positive for C3d on immunoperoxidase staining. Other dermatologic inflammatory conditions stain positively with C3d, such as systemic lupus erythematosus, discoid lupus erythematosus, subacute cutaneous lupus erythematosus, and dermatomysositis.¹³ The staining for these diseases correlates with the site of the associated inflammatory component seen on hematoxylin and eosin staining. The staining of C3d along the basement membrane of stratified squamous epithelium in the lymphoepithelial cyst of the pancreas seen in our patient closely resembles the staining seen in cutaneous BP.

A proposed mechanism for BP in our patient would be exposure of BP-1 antigen in the pancreatic cyst leading to antibody recognition and C3 deposition along the basement membrane in the cyst, as evidenced by C3d immunoperoxidase staining. The IgG and C3 deposition along the cutaneous basement membrane would then represent a systemic response to the antigen exposure in the cyst. Thus, the lymphoepithelial cyst provided the immunologic stimulus for the development of the cutaneous BP. This theory is based on the observation of our patient’s rapid improvement without a change in his treatment regimen immediately after surgical excision of the cyst.

Despite the plausibility of our hypothesis, several questions remain regarding the validity of our assumptions. Although sensitive for C3 deposition, C3d immunoperoxidase staining is not specific for BP. If the proposed mechanism for causation is true, one might have expected that a subepithelial cleft along the basement membrane of the pancreatic cyst would be observed, which was not seen. A repeat BP antigen antibody was not obtained, which would have been helpful in determining if there was clearance of the antibody that would have correlated with the clinical resolution of the BP lesions.

Conclusion

Our case suggests that paraneoplastic BP is a genuine entity. Indeed, the primary tumor itself may be the immunologic stimulus in the development of BP. Recalcitrant BP should raise the question of a neoplastic process that is exposing the BP antigen. If a thorough review of systems accompanied by corroborating laboratory studies suggests a neoplastic process, the suspect lesion should be further evaluated and surgically excised if clinically indicated. Further evaluation of neoplasms with advanced staining methods may aid in establishing the causative nature of tumors in the development of BP.

Acknowledgments

We are grateful to John Stanley, MD, and Aimee Payne, MD (both from Philadelphia, Pennsylvania), for theirinsights into this case.

Bullous pemphigoid (BP) is an acquired, autoimmune, subepidermal blistering disease that is more common in elderly patients.¹ An association with internal neoplasms and BP has been established; however, there is debate regarding the precise nature of the relationship.² Several gastrointestinal tract tumors have been associated with BP, including adenocarcinoma of the colon, adenosquamous cell carcinoma and adenocarcinoma of the stomach, adenocarcinoma of the rectum, and liver and bile duct malignancies.^3-5 Association with pancreatic neoplasms (eg, carcinoma of the pancreas) rarely has been reported.^5-7 We present an unusual case of a lymphoepithelial cyst of the pancreas in a patient with BP.

Case Report

A 67-year-old man presented with erythematous crusted plaques and pink scars over the chest, back, arms, and legs (Figure 1). A 1.5-cm tense bullous lesion was observed on the right knee. The patient’s medical history was notable for biopsy-proven BP of 8 months’ duration as well as diabetes mellitus and hypothyroidism. The patient was being followed by his surgeon for a 1.9-cm soft-tissue lesion in the pancreatic tail and was awaiting surgical excision at the time of the current presentation. The pancreatic lesion was discovered incidentally on magnetic resonance imaging performed following urologic concerns. At the current presentation, the patient’s medications included nifedipine, hydralazine, metoprolol, torsemide, aspirin, levothyroxine, atorvastatin, insulin lispro, and insulin glargine. He had previously been treated for BP with prednisone at a maximum dosage of 60 mg daily, clobetasol propionate cream 0.05%, and mupirocin ointment 2% without improvement. Because of substantial weight gain and poorly controlled diabetes, prednisone was discontinued.

Bullous pemphigoid had been diagnosed histopathologically by a prior dermatologist. Hematoxylin and eosin staining demonstrated a subepidermal separation with eosinophils within the perivascular infiltrate (Figure 2). Direct immunofluorescence was noted in a linear pattern at the dermoepidermal junction with IgG and C3. Bullous pemphigoid antigen antibodies 1 and 2 were obtained via enzyme-linked immunosorbent assay with a positive BP-1 antigen antibody of 19 U/mL (positive, >15 U/mL) and a normal BP-2 antigen antibody of less than 9 U/mL (reference range, <9 U/mL). The glucagon level was elevated at 245 pg/mL (reference range, ≤134 pg/mL).

The patient was prescribed minocycline 100 mg twice daily and niacinamide 500 mg 3 times daily. Topical treatment with clobetasol and mupirocin was continued. One month later, the patient returned with an increase in disease activity. Changes to his therapeutic regimen were deferred until after excision of the pancreatic lesion based on the decision not to start immunosuppressive therapy until the precise nature of the pancreatic lesion was determined.

The patient underwent excision of the pancreatic lesion approximately 3 months later, which proved to be a benign lymphoepithelial cyst of the pancreas. Histology of the cyst consisted of dense fibrous tissue with a squamous epithelial lining focally infiltrated by lymphocytes (Figure 3A). Immunoperoxidase staining of the cyst revealed focal linear areas of C3d staining along the basement membrane of the stratified squamous epithelium (Figure 3B).

The patient stated that his skin started to improve virtually immediately following the excision without systemic treatment for BP. On follow-up examination 3 weeks postoperatively, no bullae were observed and there was a notable decrease in erythematous crusted plaques (Figure 4).

Comment

Paraneoplastic BP has been documented; however, lymphoepithelial cysts of the pancreas in association with BP are rare. We propose that the lymphoepithelial cyst of the pancreas provided the immunologic stimulus for the development of cutaneous BP based on the observation that our patient’s condition remarkably improved with resection of the tumor.

There are fewer than 100 cases of lymphoepithelial cysts of the pancreas reported in the literature.⁸ The histologic appearance is consistent with a true cyst exhibiting a well-differentiated stratified squamous epithelium, often with keratinization, surrounded by lymphoid tissue. These tumors are most commonly seen in middle-aged men and are frequently found incidentally,^8-10 as was the case with our patient. Although histologically similar, lymphoepithelial cysts of the pancreas are considered distinct from lymphoepithelial cysts of the parotid gland or head and neck region.¹⁰ Lymphoepithelial cysts of the pancreas are unrelated to elevated glucagon levels; it is likely that our patient’s glucagon levels were associated with his history of diabetes.¹¹

In theory, any process that involves deposition of C3 should be positive for C3d on immunoperoxidase staining. Other dermatologic inflammatory conditions stain positively with C3d, such as systemic lupus erythematosus, discoid lupus erythematosus, subacute cutaneous lupus erythematosus, and dermatomysositis.¹³ The staining for these diseases correlates with the site of the associated inflammatory component seen on hematoxylin and eosin staining. The staining of C3d along the basement membrane of stratified squamous epithelium in the lymphoepithelial cyst of the pancreas seen in our patient closely resembles the staining seen in cutaneous BP.

A proposed mechanism for BP in our patient would be exposure of BP-1 antigen in the pancreatic cyst leading to antibody recognition and C3 deposition along the basement membrane in the cyst, as evidenced by C3d immunoperoxidase staining. The IgG and C3 deposition along the cutaneous basement membrane would then represent a systemic response to the antigen exposure in the cyst. Thus, the lymphoepithelial cyst provided the immunologic stimulus for the development of the cutaneous BP. This theory is based on the observation of our patient’s rapid improvement without a change in his treatment regimen immediately after surgical excision of the cyst.

Despite the plausibility of our hypothesis, several questions remain regarding the validity of our assumptions. Although sensitive for C3 deposition, C3d immunoperoxidase staining is not specific for BP. If the proposed mechanism for causation is true, one might have expected that a subepithelial cleft along the basement membrane of the pancreatic cyst would be observed, which was not seen. A repeat BP antigen antibody was not obtained, which would have been helpful in determining if there was clearance of the antibody that would have correlated with the clinical resolution of the BP lesions.

Conclusion

Our case suggests that paraneoplastic BP is a genuine entity. Indeed, the primary tumor itself may be the immunologic stimulus in the development of BP. Recalcitrant BP should raise the question of a neoplastic process that is exposing the BP antigen. If a thorough review of systems accompanied by corroborating laboratory studies suggests a neoplastic process, the suspect lesion should be further evaluated and surgically excised if clinically indicated. Further evaluation of neoplasms with advanced staining methods may aid in establishing the causative nature of tumors in the development of BP.

Acknowledgments

We are grateful to John Stanley, MD, and Aimee Payne, MD (both from Philadelphia, Pennsylvania), for theirinsights into this case.

Bullous pemphigoid (BP) is an acquired, autoimmune, subepidermal blistering disease that is more common in elderly patients.¹ An association with internal neoplasms and BP has been established; however, there is debate regarding the precise nature of the relationship.² Several gastrointestinal tract tumors have been associated with BP, including adenocarcinoma of the colon, adenosquamous cell carcinoma and adenocarcinoma of the stomach, adenocarcinoma of the rectum, and liver and bile duct malignancies.^3-5 Association with pancreatic neoplasms (eg, carcinoma of the pancreas) rarely has been reported.^5-7 We present an unusual case of a lymphoepithelial cyst of the pancreas in a patient with BP.

Case Report

A 67-year-old man presented with erythematous crusted plaques and pink scars over the chest, back, arms, and legs (Figure 1). A 1.5-cm tense bullous lesion was observed on the right knee. The patient’s medical history was notable for biopsy-proven BP of 8 months’ duration as well as diabetes mellitus and hypothyroidism. The patient was being followed by his surgeon for a 1.9-cm soft-tissue lesion in the pancreatic tail and was awaiting surgical excision at the time of the current presentation. The pancreatic lesion was discovered incidentally on magnetic resonance imaging performed following urologic concerns. At the current presentation, the patient’s medications included nifedipine, hydralazine, metoprolol, torsemide, aspirin, levothyroxine, atorvastatin, insulin lispro, and insulin glargine. He had previously been treated for BP with prednisone at a maximum dosage of 60 mg daily, clobetasol propionate cream 0.05%, and mupirocin ointment 2% without improvement. Because of substantial weight gain and poorly controlled diabetes, prednisone was discontinued.

Bullous pemphigoid had been diagnosed histopathologically by a prior dermatologist. Hematoxylin and eosin staining demonstrated a subepidermal separation with eosinophils within the perivascular infiltrate (Figure 2). Direct immunofluorescence was noted in a linear pattern at the dermoepidermal junction with IgG and C3. Bullous pemphigoid antigen antibodies 1 and 2 were obtained via enzyme-linked immunosorbent assay with a positive BP-1 antigen antibody of 19 U/mL (positive, >15 U/mL) and a normal BP-2 antigen antibody of less than 9 U/mL (reference range, <9 U/mL). The glucagon level was elevated at 245 pg/mL (reference range, ≤134 pg/mL).

The patient was prescribed minocycline 100 mg twice daily and niacinamide 500 mg 3 times daily. Topical treatment with clobetasol and mupirocin was continued. One month later, the patient returned with an increase in disease activity. Changes to his therapeutic regimen were deferred until after excision of the pancreatic lesion based on the decision not to start immunosuppressive therapy until the precise nature of the pancreatic lesion was determined.

The patient underwent excision of the pancreatic lesion approximately 3 months later, which proved to be a benign lymphoepithelial cyst of the pancreas. Histology of the cyst consisted of dense fibrous tissue with a squamous epithelial lining focally infiltrated by lymphocytes (Figure 3A). Immunoperoxidase staining of the cyst revealed focal linear areas of C3d staining along the basement membrane of the stratified squamous epithelium (Figure 3B).

The patient stated that his skin started to improve virtually immediately following the excision without systemic treatment for BP. On follow-up examination 3 weeks postoperatively, no bullae were observed and there was a notable decrease in erythematous crusted plaques (Figure 4).

Comment

Paraneoplastic BP has been documented; however, lymphoepithelial cysts of the pancreas in association with BP are rare. We propose that the lymphoepithelial cyst of the pancreas provided the immunologic stimulus for the development of cutaneous BP based on the observation that our patient’s condition remarkably improved with resection of the tumor.

There are fewer than 100 cases of lymphoepithelial cysts of the pancreas reported in the literature.⁸ The histologic appearance is consistent with a true cyst exhibiting a well-differentiated stratified squamous epithelium, often with keratinization, surrounded by lymphoid tissue. These tumors are most commonly seen in middle-aged men and are frequently found incidentally,^8-10 as was the case with our patient. Although histologically similar, lymphoepithelial cysts of the pancreas are considered distinct from lymphoepithelial cysts of the parotid gland or head and neck region.¹⁰ Lymphoepithelial cysts of the pancreas are unrelated to elevated glucagon levels; it is likely that our patient’s glucagon levels were associated with his history of diabetes.¹¹

In theory, any process that involves deposition of C3 should be positive for C3d on immunoperoxidase staining. Other dermatologic inflammatory conditions stain positively with C3d, such as systemic lupus erythematosus, discoid lupus erythematosus, subacute cutaneous lupus erythematosus, and dermatomysositis.¹³ The staining for these diseases correlates with the site of the associated inflammatory component seen on hematoxylin and eosin staining. The staining of C3d along the basement membrane of stratified squamous epithelium in the lymphoepithelial cyst of the pancreas seen in our patient closely resembles the staining seen in cutaneous BP.

A proposed mechanism for BP in our patient would be exposure of BP-1 antigen in the pancreatic cyst leading to antibody recognition and C3 deposition along the basement membrane in the cyst, as evidenced by C3d immunoperoxidase staining. The IgG and C3 deposition along the cutaneous basement membrane would then represent a systemic response to the antigen exposure in the cyst. Thus, the lymphoepithelial cyst provided the immunologic stimulus for the development of the cutaneous BP. This theory is based on the observation of our patient’s rapid improvement without a change in his treatment regimen immediately after surgical excision of the cyst.

Despite the plausibility of our hypothesis, several questions remain regarding the validity of our assumptions. Although sensitive for C3 deposition, C3d immunoperoxidase staining is not specific for BP. If the proposed mechanism for causation is true, one might have expected that a subepithelial cleft along the basement membrane of the pancreatic cyst would be observed, which was not seen. A repeat BP antigen antibody was not obtained, which would have been helpful in determining if there was clearance of the antibody that would have correlated with the clinical resolution of the BP lesions.

Conclusion

Our case suggests that paraneoplastic BP is a genuine entity. Indeed, the primary tumor itself may be the immunologic stimulus in the development of BP. Recalcitrant BP should raise the question of a neoplastic process that is exposing the BP antigen. If a thorough review of systems accompanied by corroborating laboratory studies suggests a neoplastic process, the suspect lesion should be further evaluated and surgically excised if clinically indicated. Further evaluation of neoplasms with advanced staining methods may aid in establishing the causative nature of tumors in the development of BP.

Acknowledgments

We are grateful to John Stanley, MD, and Aimee Payne, MD (both from Philadelphia, Pennsylvania), for theirinsights into this case.

Rosacea is a chronic inflammatory disorder that may negatively impact patients’ quality of life (QOL).^1,2 Papulopustular rosacea (PPR) is characterized by centrofacial inflammatory lesions and erythema as well as burning and stinging secondary to skin barrier dysfunction.^3-5 Increasing rosacea severity is associated with greater rates of anxiety and depression and lower QOL⁶ as well as low self-esteem and feelings of embarrassment.^7,8 Accordingly, assessing patient perceptions of rosacea treatments is necessary for understanding its impact on patient health.^6,9

The Rosacea International Expert Group has emphasized the need to incorporate patient assessments of disease severity and QOL when developing therapeutic strategies for rosacea.⁷ Ease of use, sensory experience, and patient preference also are important dimensions in the evaluation of topical medications, as attributes of specific formulations may affect usability, adherence, and efficacy.^10,11

An azelaic acid (AzA) 15% foam formulation, which was approved by the US Food and Drug Administration in 2015, was developed to deliver AzA in a vehicle designed to improve treatment experience in patients with mild to moderate PPR.¹² Results from a clinical trial demonstrated superiority of AzA foam to vehicle foam for primary end points that included therapeutic success rate and change in inflammatory lesion count.^13,14 Secondary end points assessed in the current analysis included patient perception of product usability, efficacy, and effect on QOL. These patient-reported outcome (PRO) results are reported here.

Methods

Study Design

The design of this phase 3 multicenter, randomized, double-blind, vehicle-controlled, parallel-group clinical trial was described in more detail in an earlier report.¹³ This study was approved by all appropriate institutional review boards. Eligible participants were 18 years and older with moderate or severe PPR, 12 to 50 inflammatory lesions, and persistent erythema with or without telangiectasia. Exclusion criteria included known nonresponse to AzA, current or prior use (within 6 weeks of randomization) of noninvestigational products to treat rosacea, and presence of other dermatoses that could interfere with rosacea evaluation.

Participants were randomized into the AzA foam or vehicle group (1:1 ratio). The study medication (0.5 g) or vehicle foam was applied twice daily to the entire face until the end of treatment (EoT) at 12 weeks. Efficacy and safety parameters were evaluated at baseline and at 4, 8, and 12 weeks of treatment, and at a follow-up visit 4 weeks after EoT (week 16).

Results for the coprimary efficacy end points—therapeutic success rate according to investigator global assessment and nominal change in inflammatory lesion count—were previously reported,¹³ as well as secondary efficacy outcomes including change in inflammatory lesion count, therapeutic response rate, and change in erythema rating.¹⁴

Patient-Reported Secondary Efficacy Outcomes

The secondary PRO end points were patient-reported global assessment of treatment response (rated as excellent, good, fair, none, or worse), global assessment of tolerability (rated as excellent, good, acceptable despite minor irritation, less acceptable due to continuous irritation, not acceptable, or no opinion), and opinion on cosmetic acceptability and practicability of product use in areas adjacent to the hairline (rated as very good, good, satisfactory, poor, or no opinion).

Additionally, QOL was measured by 3 validated standardized PRO tools, including the Rosacea Quality of Life Index (RosaQOL),¹⁵ the EuroQOL 5-dimension 5-level questionnaire (EQ-5D-5L),¹⁶ and the Dermatology Life Quality Index (DLQI). The RosaQOL is a rosacea-specific instrument assessing 3 constructs: (1) symptom, (2) emotion, and (3) function. The EQ-5D-5L questionnaire measures overall health status and comprises 5 constructs: (1) mobility, (2) self-care, (3) usual activities, (4) pain/discomfort, and (5) anxiety/depression. The DLQI is a general, dermatology-oriented instrument categorized into 6 constructs: (1) symptoms and feelings, (2) daily activities, (3) leisure, (4) work and school, (5) personal relationships, and (6) treatment.

Statistical Analyses

Patient-reported outcomes were analyzed in an exploratory manner and evaluated at EoT relative to baseline. Self-reported global assessment of treatment response and change in RosaQOL, EQ-5D-5L, and DLQI scores between AzA foam and vehicle foam groups were evaluated using the Wilcoxon rank sum test. Categorical change in the number of participants achieving an increase of 5 or more points in overall DLQI score was evaluated using a χ² test.

Safety

Safety was analyzed for all randomized patients who were dispensed any study medication. All analyses were performed using SAS version 9.2.

Results

Of the 961 participants included in the study, 483 were randomized to receive AzA foam and 478 were randomized to receive vehicle foam. The mean age was 51.5 years, and the majority of participants were female (73.0%) and white (95.5%)(Table). At baseline, 834 (86.8%) participants had moderate PPR and 127 (13.2%) had severe PPR. The mean inflammatory lesion count (SD) was 21.4 (8.9). No significant differences in baseline characteristics were observed between treatment groups.

Patient-reported global assessment of treatment response differed between treatment groups at EoT (P<.001)(Figure 1). Higher ratings of treatment response were reported among the AzA foam group (excellent, 17.2%; good, 40.0%) versus vehicle foam (excellent, 9.7%; good, 35.0%). The number of participants reporting no treatment response was 13.1% in the AzA foam group, with 1.8% reporting worsening of their condition, while 19.4% of participants in the vehicle foam group reported no response, with 6.3% reporting worsening of their condition (Figure 1).

The incidence of drug-related adverse events (AEs) was greater in the AzA foam group versus the vehicle foam group (7.7% vs 4.8%). Drug-related AEs occurring in 1% of the AzA foam group were application-site pain including tenderness, stinging, and burning (3.5% for AzA foam vs 1.3% for vehicle foam); application-site pruritus (1.4% vs 0.4%); and application-site dryness (1.0% vs 0.6%). One drug-related AE of severe intensity—application-site dermatitis—occurred in the vehicle foam group; all other drug-related AEs were mild or moderate.¹⁴ More detailed safety results are described in a previous report.¹³

Comment

The PRO outcome data reported here are consistent with previously reported statistically significant improvements in investigator-assessed primary end points for the treatment of PPR with AzA foam.^13,14 The data demonstrate that AzA foam benefits both clinical and patient-oriented dimensions of rosacea disease burden and suggest an association between positive treatment response and improved QOL.

Specifically, patient evaluation of treatment response to AzA foam was highly favorable, with 57.2% reporting excellent or good response and 85.1% reporting positive response overall. Recognizing the relapsing-remitting course of PPR, only 1.8% of the AzA foam group experienced worsening of disease at EoT.

The DLQI and RosaQOL instruments revealed notable improvements in QOL from baseline for both treatment groups. Although no significant differences in RosaQOL scores were observed between groups at EoT, significant differences in DLQI scores were detected. Almost one-quarter of participants in the AzA foam group achieved at least a 5-point improvement in DLQI score, exceeding the 4-point threshold for clinically meaningful change.¹⁷ Although little change in EQ-5D-5L scores was observed at EoT for both groups with no between-group differences, this finding is not unexpected, as this instrument assesses QOL dimensions such as loss of function, mobility, and ability to wash or dress, which are unlikely to be compromised in most rosacea patients.

Our results also underscore the importance of vehicle in the treatment of compromised skin. Studies of topical treatments for other dermatoses suggest that vehicle properties may reduce disease severity and improve QOL independent of active ingredients.^10,18 For example, ease of application, minimal residue, and less time spent in application may explain the superiority of foam to other vehicles in the treatment of psoriasis.¹⁸ Our data demonstrating high cosmetic favorability of AzA foam are consistent with these prior observations. Increased tolerability of foam formulations also may affect response to treatment, in part by supporting adherence.¹⁸ Most participants receiving AzA foam described tolerability as excellent or good, and the discontinuation rate was low (1.2% of participants in the AzA foam group left the study due to AEs) in the setting of near-complete dosage administration (97% of expected doses applied).¹³

Conclusion

These results indicate that use of AzA foam as well as its novel vehicle results in high patient satisfaction and improved QOL. Although additional research is necessary to further delineate the relationship between PROs and other measures of clinical efficacy, our data demonstrate a positive treatment experience as perceived by patients that parallels the clinical efficacy of AzA foam for the treatment of PPR.^13,14

Acknowledgment

Editorial support through inVentiv Medical Communications (New York, New York) was provided by Bayer Pharmaceuticals.

Rosacea is a chronic inflammatory disorder that may negatively impact patients’ quality of life (QOL).^1,2 Papulopustular rosacea (PPR) is characterized by centrofacial inflammatory lesions and erythema as well as burning and stinging secondary to skin barrier dysfunction.^3-5 Increasing rosacea severity is associated with greater rates of anxiety and depression and lower QOL⁶ as well as low self-esteem and feelings of embarrassment.^7,8 Accordingly, assessing patient perceptions of rosacea treatments is necessary for understanding its impact on patient health.^6,9

The Rosacea International Expert Group has emphasized the need to incorporate patient assessments of disease severity and QOL when developing therapeutic strategies for rosacea.⁷ Ease of use, sensory experience, and patient preference also are important dimensions in the evaluation of topical medications, as attributes of specific formulations may affect usability, adherence, and efficacy.^10,11

An azelaic acid (AzA) 15% foam formulation, which was approved by the US Food and Drug Administration in 2015, was developed to deliver AzA in a vehicle designed to improve treatment experience in patients with mild to moderate PPR.¹² Results from a clinical trial demonstrated superiority of AzA foam to vehicle foam for primary end points that included therapeutic success rate and change in inflammatory lesion count.^13,14 Secondary end points assessed in the current analysis included patient perception of product usability, efficacy, and effect on QOL. These patient-reported outcome (PRO) results are reported here.

Methods

Study Design

The design of this phase 3 multicenter, randomized, double-blind, vehicle-controlled, parallel-group clinical trial was described in more detail in an earlier report.¹³ This study was approved by all appropriate institutional review boards. Eligible participants were 18 years and older with moderate or severe PPR, 12 to 50 inflammatory lesions, and persistent erythema with or without telangiectasia. Exclusion criteria included known nonresponse to AzA, current or prior use (within 6 weeks of randomization) of noninvestigational products to treat rosacea, and presence of other dermatoses that could interfere with rosacea evaluation.

Participants were randomized into the AzA foam or vehicle group (1:1 ratio). The study medication (0.5 g) or vehicle foam was applied twice daily to the entire face until the end of treatment (EoT) at 12 weeks. Efficacy and safety parameters were evaluated at baseline and at 4, 8, and 12 weeks of treatment, and at a follow-up visit 4 weeks after EoT (week 16).

Results for the coprimary efficacy end points—therapeutic success rate according to investigator global assessment and nominal change in inflammatory lesion count—were previously reported,¹³ as well as secondary efficacy outcomes including change in inflammatory lesion count, therapeutic response rate, and change in erythema rating.¹⁴

Patient-Reported Secondary Efficacy Outcomes

The secondary PRO end points were patient-reported global assessment of treatment response (rated as excellent, good, fair, none, or worse), global assessment of tolerability (rated as excellent, good, acceptable despite minor irritation, less acceptable due to continuous irritation, not acceptable, or no opinion), and opinion on cosmetic acceptability and practicability of product use in areas adjacent to the hairline (rated as very good, good, satisfactory, poor, or no opinion).

Additionally, QOL was measured by 3 validated standardized PRO tools, including the Rosacea Quality of Life Index (RosaQOL),¹⁵ the EuroQOL 5-dimension 5-level questionnaire (EQ-5D-5L),¹⁶ and the Dermatology Life Quality Index (DLQI). The RosaQOL is a rosacea-specific instrument assessing 3 constructs: (1) symptom, (2) emotion, and (3) function. The EQ-5D-5L questionnaire measures overall health status and comprises 5 constructs: (1) mobility, (2) self-care, (3) usual activities, (4) pain/discomfort, and (5) anxiety/depression. The DLQI is a general, dermatology-oriented instrument categorized into 6 constructs: (1) symptoms and feelings, (2) daily activities, (3) leisure, (4) work and school, (5) personal relationships, and (6) treatment.

Statistical Analyses

Patient-reported outcomes were analyzed in an exploratory manner and evaluated at EoT relative to baseline. Self-reported global assessment of treatment response and change in RosaQOL, EQ-5D-5L, and DLQI scores between AzA foam and vehicle foam groups were evaluated using the Wilcoxon rank sum test. Categorical change in the number of participants achieving an increase of 5 or more points in overall DLQI score was evaluated using a χ² test.

Safety

Safety was analyzed for all randomized patients who were dispensed any study medication. All analyses were performed using SAS version 9.2.

Results

Of the 961 participants included in the study, 483 were randomized to receive AzA foam and 478 were randomized to receive vehicle foam. The mean age was 51.5 years, and the majority of participants were female (73.0%) and white (95.5%)(Table). At baseline, 834 (86.8%) participants had moderate PPR and 127 (13.2%) had severe PPR. The mean inflammatory lesion count (SD) was 21.4 (8.9). No significant differences in baseline characteristics were observed between treatment groups.

Patient-reported global assessment of treatment response differed between treatment groups at EoT (P<.001)(Figure 1). Higher ratings of treatment response were reported among the AzA foam group (excellent, 17.2%; good, 40.0%) versus vehicle foam (excellent, 9.7%; good, 35.0%). The number of participants reporting no treatment response was 13.1% in the AzA foam group, with 1.8% reporting worsening of their condition, while 19.4% of participants in the vehicle foam group reported no response, with 6.3% reporting worsening of their condition (Figure 1).

The incidence of drug-related adverse events (AEs) was greater in the AzA foam group versus the vehicle foam group (7.7% vs 4.8%). Drug-related AEs occurring in 1% of the AzA foam group were application-site pain including tenderness, stinging, and burning (3.5% for AzA foam vs 1.3% for vehicle foam); application-site pruritus (1.4% vs 0.4%); and application-site dryness (1.0% vs 0.6%). One drug-related AE of severe intensity—application-site dermatitis—occurred in the vehicle foam group; all other drug-related AEs were mild or moderate.¹⁴ More detailed safety results are described in a previous report.¹³

Comment

The PRO outcome data reported here are consistent with previously reported statistically significant improvements in investigator-assessed primary end points for the treatment of PPR with AzA foam.^13,14 The data demonstrate that AzA foam benefits both clinical and patient-oriented dimensions of rosacea disease burden and suggest an association between positive treatment response and improved QOL.

Specifically, patient evaluation of treatment response to AzA foam was highly favorable, with 57.2% reporting excellent or good response and 85.1% reporting positive response overall. Recognizing the relapsing-remitting course of PPR, only 1.8% of the AzA foam group experienced worsening of disease at EoT.

The DLQI and RosaQOL instruments revealed notable improvements in QOL from baseline for both treatment groups. Although no significant differences in RosaQOL scores were observed between groups at EoT, significant differences in DLQI scores were detected. Almost one-quarter of participants in the AzA foam group achieved at least a 5-point improvement in DLQI score, exceeding the 4-point threshold for clinically meaningful change.¹⁷ Although little change in EQ-5D-5L scores was observed at EoT for both groups with no between-group differences, this finding is not unexpected, as this instrument assesses QOL dimensions such as loss of function, mobility, and ability to wash or dress, which are unlikely to be compromised in most rosacea patients.

Our results also underscore the importance of vehicle in the treatment of compromised skin. Studies of topical treatments for other dermatoses suggest that vehicle properties may reduce disease severity and improve QOL independent of active ingredients.^10,18 For example, ease of application, minimal residue, and less time spent in application may explain the superiority of foam to other vehicles in the treatment of psoriasis.¹⁸ Our data demonstrating high cosmetic favorability of AzA foam are consistent with these prior observations. Increased tolerability of foam formulations also may affect response to treatment, in part by supporting adherence.¹⁸ Most participants receiving AzA foam described tolerability as excellent or good, and the discontinuation rate was low (1.2% of participants in the AzA foam group left the study due to AEs) in the setting of near-complete dosage administration (97% of expected doses applied).¹³

Conclusion

These results indicate that use of AzA foam as well as its novel vehicle results in high patient satisfaction and improved QOL. Although additional research is necessary to further delineate the relationship between PROs and other measures of clinical efficacy, our data demonstrate a positive treatment experience as perceived by patients that parallels the clinical efficacy of AzA foam for the treatment of PPR.^13,14

Acknowledgment

Editorial support through inVentiv Medical Communications (New York, New York) was provided by Bayer Pharmaceuticals.

Rosacea is a chronic inflammatory disorder that may negatively impact patients’ quality of life (QOL).^1,2 Papulopustular rosacea (PPR) is characterized by centrofacial inflammatory lesions and erythema as well as burning and stinging secondary to skin barrier dysfunction.^3-5 Increasing rosacea severity is associated with greater rates of anxiety and depression and lower QOL⁶ as well as low self-esteem and feelings of embarrassment.^7,8 Accordingly, assessing patient perceptions of rosacea treatments is necessary for understanding its impact on patient health.^6,9

The Rosacea International Expert Group has emphasized the need to incorporate patient assessments of disease severity and QOL when developing therapeutic strategies for rosacea.⁷ Ease of use, sensory experience, and patient preference also are important dimensions in the evaluation of topical medications, as attributes of specific formulations may affect usability, adherence, and efficacy.^10,11

An azelaic acid (AzA) 15% foam formulation, which was approved by the US Food and Drug Administration in 2015, was developed to deliver AzA in a vehicle designed to improve treatment experience in patients with mild to moderate PPR.¹² Results from a clinical trial demonstrated superiority of AzA foam to vehicle foam for primary end points that included therapeutic success rate and change in inflammatory lesion count.^13,14 Secondary end points assessed in the current analysis included patient perception of product usability, efficacy, and effect on QOL. These patient-reported outcome (PRO) results are reported here.

Methods

Study Design

The design of this phase 3 multicenter, randomized, double-blind, vehicle-controlled, parallel-group clinical trial was described in more detail in an earlier report.¹³ This study was approved by all appropriate institutional review boards. Eligible participants were 18 years and older with moderate or severe PPR, 12 to 50 inflammatory lesions, and persistent erythema with or without telangiectasia. Exclusion criteria included known nonresponse to AzA, current or prior use (within 6 weeks of randomization) of noninvestigational products to treat rosacea, and presence of other dermatoses that could interfere with rosacea evaluation.

Participants were randomized into the AzA foam or vehicle group (1:1 ratio). The study medication (0.5 g) or vehicle foam was applied twice daily to the entire face until the end of treatment (EoT) at 12 weeks. Efficacy and safety parameters were evaluated at baseline and at 4, 8, and 12 weeks of treatment, and at a follow-up visit 4 weeks after EoT (week 16).

Results for the coprimary efficacy end points—therapeutic success rate according to investigator global assessment and nominal change in inflammatory lesion count—were previously reported,¹³ as well as secondary efficacy outcomes including change in inflammatory lesion count, therapeutic response rate, and change in erythema rating.¹⁴

Patient-Reported Secondary Efficacy Outcomes

The secondary PRO end points were patient-reported global assessment of treatment response (rated as excellent, good, fair, none, or worse), global assessment of tolerability (rated as excellent, good, acceptable despite minor irritation, less acceptable due to continuous irritation, not acceptable, or no opinion), and opinion on cosmetic acceptability and practicability of product use in areas adjacent to the hairline (rated as very good, good, satisfactory, poor, or no opinion).

Additionally, QOL was measured by 3 validated standardized PRO tools, including the Rosacea Quality of Life Index (RosaQOL),¹⁵ the EuroQOL 5-dimension 5-level questionnaire (EQ-5D-5L),¹⁶ and the Dermatology Life Quality Index (DLQI). The RosaQOL is a rosacea-specific instrument assessing 3 constructs: (1) symptom, (2) emotion, and (3) function. The EQ-5D-5L questionnaire measures overall health status and comprises 5 constructs: (1) mobility, (2) self-care, (3) usual activities, (4) pain/discomfort, and (5) anxiety/depression. The DLQI is a general, dermatology-oriented instrument categorized into 6 constructs: (1) symptoms and feelings, (2) daily activities, (3) leisure, (4) work and school, (5) personal relationships, and (6) treatment.

Statistical Analyses

Patient-reported outcomes were analyzed in an exploratory manner and evaluated at EoT relative to baseline. Self-reported global assessment of treatment response and change in RosaQOL, EQ-5D-5L, and DLQI scores between AzA foam and vehicle foam groups were evaluated using the Wilcoxon rank sum test. Categorical change in the number of participants achieving an increase of 5 or more points in overall DLQI score was evaluated using a χ² test.

Safety

Safety was analyzed for all randomized patients who were dispensed any study medication. All analyses were performed using SAS version 9.2.

Results

Of the 961 participants included in the study, 483 were randomized to receive AzA foam and 478 were randomized to receive vehicle foam. The mean age was 51.5 years, and the majority of participants were female (73.0%) and white (95.5%)(Table). At baseline, 834 (86.8%) participants had moderate PPR and 127 (13.2%) had severe PPR. The mean inflammatory lesion count (SD) was 21.4 (8.9). No significant differences in baseline characteristics were observed between treatment groups.

Patient-reported global assessment of treatment response differed between treatment groups at EoT (P<.001)(Figure 1). Higher ratings of treatment response were reported among the AzA foam group (excellent, 17.2%; good, 40.0%) versus vehicle foam (excellent, 9.7%; good, 35.0%). The number of participants reporting no treatment response was 13.1% in the AzA foam group, with 1.8% reporting worsening of their condition, while 19.4% of participants in the vehicle foam group reported no response, with 6.3% reporting worsening of their condition (Figure 1).

The incidence of drug-related adverse events (AEs) was greater in the AzA foam group versus the vehicle foam group (7.7% vs 4.8%). Drug-related AEs occurring in 1% of the AzA foam group were application-site pain including tenderness, stinging, and burning (3.5% for AzA foam vs 1.3% for vehicle foam); application-site pruritus (1.4% vs 0.4%); and application-site dryness (1.0% vs 0.6%). One drug-related AE of severe intensity—application-site dermatitis—occurred in the vehicle foam group; all other drug-related AEs were mild or moderate.¹⁴ More detailed safety results are described in a previous report.¹³

Comment

The PRO outcome data reported here are consistent with previously reported statistically significant improvements in investigator-assessed primary end points for the treatment of PPR with AzA foam.^13,14 The data demonstrate that AzA foam benefits both clinical and patient-oriented dimensions of rosacea disease burden and suggest an association between positive treatment response and improved QOL.

Specifically, patient evaluation of treatment response to AzA foam was highly favorable, with 57.2% reporting excellent or good response and 85.1% reporting positive response overall. Recognizing the relapsing-remitting course of PPR, only 1.8% of the AzA foam group experienced worsening of disease at EoT.

The DLQI and RosaQOL instruments revealed notable improvements in QOL from baseline for both treatment groups. Although no significant differences in RosaQOL scores were observed between groups at EoT, significant differences in DLQI scores were detected. Almost one-quarter of participants in the AzA foam group achieved at least a 5-point improvement in DLQI score, exceeding the 4-point threshold for clinically meaningful change.¹⁷ Although little change in EQ-5D-5L scores was observed at EoT for both groups with no between-group differences, this finding is not unexpected, as this instrument assesses QOL dimensions such as loss of function, mobility, and ability to wash or dress, which are unlikely to be compromised in most rosacea patients.

Our results also underscore the importance of vehicle in the treatment of compromised skin. Studies of topical treatments for other dermatoses suggest that vehicle properties may reduce disease severity and improve QOL independent of active ingredients.^10,18 For example, ease of application, minimal residue, and less time spent in application may explain the superiority of foam to other vehicles in the treatment of psoriasis.¹⁸ Our data demonstrating high cosmetic favorability of AzA foam are consistent with these prior observations. Increased tolerability of foam formulations also may affect response to treatment, in part by supporting adherence.¹⁸ Most participants receiving AzA foam described tolerability as excellent or good, and the discontinuation rate was low (1.2% of participants in the AzA foam group left the study due to AEs) in the setting of near-complete dosage administration (97% of expected doses applied).¹³

Conclusion

These results indicate that use of AzA foam as well as its novel vehicle results in high patient satisfaction and improved QOL. Although additional research is necessary to further delineate the relationship between PROs and other measures of clinical efficacy, our data demonstrate a positive treatment experience as perceived by patients that parallels the clinical efficacy of AzA foam for the treatment of PPR.^13,14

Acknowledgment

Editorial support through inVentiv Medical Communications (New York, New York) was provided by Bayer Pharmaceuticals.

Folliculotropic Mycosis Fungoides

Folliculotropic mycosis fungoides (FMF) is a variant of mycosis fungoides (MF) that occurs mostly in adults with a male predilection. The disease clinically favors the head and neck. Patients commonly present with pruritic papules that often are grouped, alopecia, and frequent secondary bacterial infections. Less commonly patients present with acneiform lesions and mucinorrhea. Patients often experience more pruritus in FMF than in classic MF, which can provide a good means of assessing disease activity. Disease-specific 5-year survival is approximately 70% to 80%, which is worse than classic plaque-stage MF and similar to tumor-stage MF.¹

Treatment of FMF differs from classic MF in that the lesions are less responsive to skin-targeted therapies due to the perifollicular nature of dermal infiltrates. Superficial skin lesions can be treated with psoralen plus UVA (PUVA) therapy. Other options include PUVA in combination with interferon alfa or retinoids and local radiotherapy for solitary thick tumors; however, in patients who have more infiltrative skin lesions or had PUVA therapy that failed, total skin electron beam therapy may be required.²

On histologic examination, there typically is perivascular and periadnexal localization of dermal infiltrates with varied involvement of the follicular epithelium and damage to hair follicles by atypical small, medium, and large hyperchromatic lymphocytes with cerebriform nuclei. Mucinous degeneration of the follicular epithelium can be seen, as highlighted on Alcian blue staining, and a mixed infiltrate of eosinophils and plasma cells often is present (quiz image and Figure 1). Frequent sparing of the epidermis is noteworthy.^2-4 In most cases, the neoplastic T lymphocytes are characterized by a CD3⁺CD4⁺CD8^-immunophenotype as is seen in classic MF. Sometimes an admixture of CD30⁺ blast cells is seen.¹

Histologic differential considerations for FMF include eosinophilic pustular folliculitis (EPF), primary follicular mucinosis, lupus erythematosus, and pityrosporum folliculitis.

Eosinophilic pustular folliculitis has several clinical subtypes, such as classic Ofuji disease and immunosuppression-associated EPF secondary to human immunodeficiency virus. Histologically, EPF is characterized by spongiosis of the hair follicle epithelium with exocytosis of a mixed infiltrate of lymphocytes and eosinophils extending from the sebaceous gland and its duct to the infundibulum with formation of hallmark eosinophilic pustules (Figure 2). Infiltration of neutrophils in inflamed lesions generally is seen. Eosinophilic pustular folliculitis is an important differential for FMF, as follicular mucinosis has been observed in lesions of EPF.⁵ Both EPF and FMF can exhibit eosinophils and lymphocytes in the upper dermis, spongiosis of the hair follicle epithelium, and mucinous degeneration of follicles,⁶ though lymphocytic atypia and relatively fewer eosinophils are suggestive of the latter.

Photograph courtesy of Brian Swick, MD (Iowa City, Iowa).

Primary follicular mucinosis (PFM) tends to occur as a solitary lesion in younger female patients in contrast to the multiple lesions that typically appear in older male patients with FMF. Histologically, PFM usually manifests as large, cystic, mucin-filled spaces and polyclonal perivascular and periadnexal lymphocytic infiltrate without notable cellular atypia or epidermotropism (Figure 3). Because follicular mucinosis is a common feature of FMF, its distinction from PFM can be challenging and often is aided by the absence of cellular atypia and relatively mild lymphocytic infiltrate in the latter.⁷

Photograph courtesy of Brian Swick, MD (Iowa City, Iowa).

Cutaneous lupus erythematosus with its characteristic folliculocentric lymphocytic infiltration and associated dermal mucin also qualifies as a potential differential possibility for FMF; however, the perivascular and periadnexal pattern of lymphocytic infiltration as well as the localization of mucin to the reticular dermal interstitium^8,9 are key histopathologic distinctions (Figure 4). Furthermore, although the histologic presentation of lupus erythematosus can be variable, it also classically shows interface dermatitis, basement membrane thickening, and follicular plugging.

Photograph courtesy of Brian Swick, MD (Iowa City, Iowa).

Pityrosporum folliculitis is the most common cause of fungal folliculitis and is caused by the Malassezia species. On histology, there typically is an unremarkable epithelium with plugged follicles and suppurative folliculitis. Serial sections of the biopsy specimen often are required to identify dilated, follicle-containing, budding yeast cells (Figure 5). Organisms are located predominantly within the infundibulum and orifice of follicular lumen, are positive for periodic acid-Schiff, and are diastase resistant.¹⁰

Photograph courtesy of Brian Swick, MD (Iowa City, Iowa).

Folliculotropic Mycosis Fungoides

Folliculotropic mycosis fungoides (FMF) is a variant of mycosis fungoides (MF) that occurs mostly in adults with a male predilection. The disease clinically favors the head and neck. Patients commonly present with pruritic papules that often are grouped, alopecia, and frequent secondary bacterial infections. Less commonly patients present with acneiform lesions and mucinorrhea. Patients often experience more pruritus in FMF than in classic MF, which can provide a good means of assessing disease activity. Disease-specific 5-year survival is approximately 70% to 80%, which is worse than classic plaque-stage MF and similar to tumor-stage MF.¹

Treatment of FMF differs from classic MF in that the lesions are less responsive to skin-targeted therapies due to the perifollicular nature of dermal infiltrates. Superficial skin lesions can be treated with psoralen plus UVA (PUVA) therapy. Other options include PUVA in combination with interferon alfa or retinoids and local radiotherapy for solitary thick tumors; however, in patients who have more infiltrative skin lesions or had PUVA therapy that failed, total skin electron beam therapy may be required.²

On histologic examination, there typically is perivascular and periadnexal localization of dermal infiltrates with varied involvement of the follicular epithelium and damage to hair follicles by atypical small, medium, and large hyperchromatic lymphocytes with cerebriform nuclei. Mucinous degeneration of the follicular epithelium can be seen, as highlighted on Alcian blue staining, and a mixed infiltrate of eosinophils and plasma cells often is present (quiz image and Figure 1). Frequent sparing of the epidermis is noteworthy.^2-4 In most cases, the neoplastic T lymphocytes are characterized by a CD3⁺CD4⁺CD8^-immunophenotype as is seen in classic MF. Sometimes an admixture of CD30⁺ blast cells is seen.¹

Histologic differential considerations for FMF include eosinophilic pustular folliculitis (EPF), primary follicular mucinosis, lupus erythematosus, and pityrosporum folliculitis.

Eosinophilic pustular folliculitis has several clinical subtypes, such as classic Ofuji disease and immunosuppression-associated EPF secondary to human immunodeficiency virus. Histologically, EPF is characterized by spongiosis of the hair follicle epithelium with exocytosis of a mixed infiltrate of lymphocytes and eosinophils extending from the sebaceous gland and its duct to the infundibulum with formation of hallmark eosinophilic pustules (Figure 2). Infiltration of neutrophils in inflamed lesions generally is seen. Eosinophilic pustular folliculitis is an important differential for FMF, as follicular mucinosis has been observed in lesions of EPF.⁵ Both EPF and FMF can exhibit eosinophils and lymphocytes in the upper dermis, spongiosis of the hair follicle epithelium, and mucinous degeneration of follicles,⁶ though lymphocytic atypia and relatively fewer eosinophils are suggestive of the latter.

Photograph courtesy of Brian Swick, MD (Iowa City, Iowa).

Primary follicular mucinosis (PFM) tends to occur as a solitary lesion in younger female patients in contrast to the multiple lesions that typically appear in older male patients with FMF. Histologically, PFM usually manifests as large, cystic, mucin-filled spaces and polyclonal perivascular and periadnexal lymphocytic infiltrate without notable cellular atypia or epidermotropism (Figure 3). Because follicular mucinosis is a common feature of FMF, its distinction from PFM can be challenging and often is aided by the absence of cellular atypia and relatively mild lymphocytic infiltrate in the latter.⁷

Photograph courtesy of Brian Swick, MD (Iowa City, Iowa).

Cutaneous lupus erythematosus with its characteristic folliculocentric lymphocytic infiltration and associated dermal mucin also qualifies as a potential differential possibility for FMF; however, the perivascular and periadnexal pattern of lymphocytic infiltration as well as the localization of mucin to the reticular dermal interstitium^8,9 are key histopathologic distinctions (Figure 4). Furthermore, although the histologic presentation of lupus erythematosus can be variable, it also classically shows interface dermatitis, basement membrane thickening, and follicular plugging.

Photograph courtesy of Brian Swick, MD (Iowa City, Iowa).

Pityrosporum folliculitis is the most common cause of fungal folliculitis and is caused by the Malassezia species. On histology, there typically is an unremarkable epithelium with plugged follicles and suppurative folliculitis. Serial sections of the biopsy specimen often are required to identify dilated, follicle-containing, budding yeast cells (Figure 5). Organisms are located predominantly within the infundibulum and orifice of follicular lumen, are positive for periodic acid-Schiff, and are diastase resistant.¹⁰

Photograph courtesy of Brian Swick, MD (Iowa City, Iowa).

Folliculotropic Mycosis Fungoides

Folliculotropic mycosis fungoides (FMF) is a variant of mycosis fungoides (MF) that occurs mostly in adults with a male predilection. The disease clinically favors the head and neck. Patients commonly present with pruritic papules that often are grouped, alopecia, and frequent secondary bacterial infections. Less commonly patients present with acneiform lesions and mucinorrhea. Patients often experience more pruritus in FMF than in classic MF, which can provide a good means of assessing disease activity. Disease-specific 5-year survival is approximately 70% to 80%, which is worse than classic plaque-stage MF and similar to tumor-stage MF.¹

Treatment of FMF differs from classic MF in that the lesions are less responsive to skin-targeted therapies due to the perifollicular nature of dermal infiltrates. Superficial skin lesions can be treated with psoralen plus UVA (PUVA) therapy. Other options include PUVA in combination with interferon alfa or retinoids and local radiotherapy for solitary thick tumors; however, in patients who have more infiltrative skin lesions or had PUVA therapy that failed, total skin electron beam therapy may be required.²

On histologic examination, there typically is perivascular and periadnexal localization of dermal infiltrates with varied involvement of the follicular epithelium and damage to hair follicles by atypical small, medium, and large hyperchromatic lymphocytes with cerebriform nuclei. Mucinous degeneration of the follicular epithelium can be seen, as highlighted on Alcian blue staining, and a mixed infiltrate of eosinophils and plasma cells often is present (quiz image and Figure 1). Frequent sparing of the epidermis is noteworthy.^2-4 In most cases, the neoplastic T lymphocytes are characterized by a CD3⁺CD4⁺CD8^-immunophenotype as is seen in classic MF. Sometimes an admixture of CD30⁺ blast cells is seen.¹

Histologic differential considerations for FMF include eosinophilic pustular folliculitis (EPF), primary follicular mucinosis, lupus erythematosus, and pityrosporum folliculitis.

Eosinophilic pustular folliculitis has several clinical subtypes, such as classic Ofuji disease and immunosuppression-associated EPF secondary to human immunodeficiency virus. Histologically, EPF is characterized by spongiosis of the hair follicle epithelium with exocytosis of a mixed infiltrate of lymphocytes and eosinophils extending from the sebaceous gland and its duct to the infundibulum with formation of hallmark eosinophilic pustules (Figure 2). Infiltration of neutrophils in inflamed lesions generally is seen. Eosinophilic pustular folliculitis is an important differential for FMF, as follicular mucinosis has been observed in lesions of EPF.⁵ Both EPF and FMF can exhibit eosinophils and lymphocytes in the upper dermis, spongiosis of the hair follicle epithelium, and mucinous degeneration of follicles,⁶ though lymphocytic atypia and relatively fewer eosinophils are suggestive of the latter.

Photograph courtesy of Brian Swick, MD (Iowa City, Iowa).

Primary follicular mucinosis (PFM) tends to occur as a solitary lesion in younger female patients in contrast to the multiple lesions that typically appear in older male patients with FMF. Histologically, PFM usually manifests as large, cystic, mucin-filled spaces and polyclonal perivascular and periadnexal lymphocytic infiltrate without notable cellular atypia or epidermotropism (Figure 3). Because follicular mucinosis is a common feature of FMF, its distinction from PFM can be challenging and often is aided by the absence of cellular atypia and relatively mild lymphocytic infiltrate in the latter.⁷

Photograph courtesy of Brian Swick, MD (Iowa City, Iowa).

Cutaneous lupus erythematosus with its characteristic folliculocentric lymphocytic infiltration and associated dermal mucin also qualifies as a potential differential possibility for FMF; however, the perivascular and periadnexal pattern of lymphocytic infiltration as well as the localization of mucin to the reticular dermal interstitium^8,9 are key histopathologic distinctions (Figure 4). Furthermore, although the histologic presentation of lupus erythematosus can be variable, it also classically shows interface dermatitis, basement membrane thickening, and follicular plugging.

Photograph courtesy of Brian Swick, MD (Iowa City, Iowa).

Pityrosporum folliculitis is the most common cause of fungal folliculitis and is caused by the Malassezia species. On histology, there typically is an unremarkable epithelium with plugged follicles and suppurative folliculitis. Serial sections of the biopsy specimen often are required to identify dilated, follicle-containing, budding yeast cells (Figure 5). Organisms are located predominantly within the infundibulum and orifice of follicular lumen, are positive for periodic acid-Schiff, and are diastase resistant.¹⁰

Photograph courtesy of Brian Swick, MD (Iowa City, Iowa).

Advances in medical biotechnologies, data-gathering techniques, and -omics technologies have resulted in the broader understanding of disease pathology and treatment and have facilitated the individualization of health care plans to meet the unique needs of each patient. Military medicine often has been on the forefront of medical technology, disease understanding, and clinical care both on and off the battlefield, in large part due to the unique resources available in the military health care system. These resources allow investigators the ability to integrate vast amounts of epidemiologic data with an extensive biological sample database of its service members, which in the modern age has translated into advances in the understanding of melanoma and the treatment of scars.

History of Research in the Military

Starting in the 1950s, the US Department of Defense (DoD) started to collect serum samples of its service members for the purpose of research.¹ It was not until 1985 that the DoD implemented a long-term frozen storage system for serum samples obtained through mandatory screening for human immunodeficiency virus (HIV) in service members.² Subsequently, the Department of Defense Serum Repository (DoDSR) was officially established in 1989 as a central archive for the long-term storage of serum obtained from active-duty and reserve service members in the US Navy, Army, and Marines.^2,3 In the mid-1990s, the DoDSR expanded its capabilities to include the storage of serum samples from all military members, including the US Air Force, obtained predeployment and postdeployment.^3,4 At that time, a records-keeping system was established, now known as the Defense Medical Surveillance System (DMSS). The creation of the DMSS provided an extensive epidemiologic database that provided valuable information such as demographic data, service records, deployment data, reportable medical events, exposure history, and vaccination records, which could be linked to the serum samples of each service member.^2-4 Since 2008, the responsibilities of maintaining the DoDSR and the DMSS were transferred to the Armed Forces Health Surveillance Center (AFHSC).⁵

There have been several other databases created over the years that provide additional support and resources to military investigators. The Automated Central Tumor Registry and Department of Pathology and Area Laboratory Services both help investigators to track the incidence of specific cancers in the military population and provide them with pathologic specimens. Additionally, electronic medical records including the composite health care system and the Armed Forces Health Longitudinal Technology Application supplemented with insurance claims data accessible from the Military Health System Management and Reporting Tool (M2) database have made it possible to track patient data.

Utilization of Military Research Resources

Today, the DoDSR is a secure facility that maintains more than 56 million serum specimens from more than 11 million individuals in –30°C freezers, making it one of the largest repositories in the world.^3,6 Each serum sample is linked with an individual’s DMSS record, providing a way for investigators to study how external factors such as deployment history, occupation, and exposure history relate to an individual’s unique genetic and physiological makeup. Furthermore, these data can be used for seroepidemiologic investigations that contribute to all facets of clinical care. The AFHSC routinely publishes findings related to notifiable diseases, disease outbreaks, and disease trends in a monthly report.⁷

There are strict guidelines in place that limit access to the DoDSR and service members’ data. Use of the repository for information directly related to a patient’s health care is one reason for access, such as analyzing serum for antibodies and seroconversion to assist in the diagnosis of a disease such as HIV. Another reason would be to obtain information needed for criminal investigations and prosecution. Typically, these types of requests require a judge-issued court order and approval by the Assistant Secretary of Defense for Health Affairs.⁴ The DoDSR also is used to study force health protection issues, such as infectious disease incidence and disease prevalence in the military population.

Obtaining access to the DoDSR and service members’ data for research purposes requires that the principal investigator be a DoD employee. Each research proposal is reviewed by members of the AFHSC to determine if the DoDSR is able to meet the demands of the project, including having the appropriate number of serum samples and supporting epidemiologic data available. The AFHSC provides a letter of support if it deems the project to be in line with its current resources and capabilities. Each research proposal is then sent to an institutional review board (IRB) to determine if the study is exempt or needs to go through a full IRB review process. A study might be exempt if the investigators are not obtaining data through interaction with living individuals or not having access to any identifiable protected health information associated with the samples.⁶ Regardless of whether the study is exempt or not exempt, the AFHSC will de-identify each sample before releasing the samples to the investigators by using a coding system to shield the patient’s identity from the investigator.

Resources within the military medical research system provide investigators with access to an extensive biorepository of serum and linked epidemiological data. Samples from the DoDSR have been used in no less than 75 peer-reviewed publications since 1985.^8,9 Several of these studies have been influential in expanding knowledge about conditions seen more commonly in the military population such as stress fractures, traumatic brain injuries, posttraumatic stress disorder, and suicide.⁸ Additionally, DoDSR samples have been used to form military vaccination policies and track both infectious and noninfectious conditions in the military; for example, during the H1N1 influenza virus outbreak of 2009, AFHSC was essential in helping to limit the spread of the virus within the military community by using its data and collaborating with groups such as the Centers for Disease Control and Prevention to develop a plan for disease surveillance and control.⁵

Several military research resources are currently being used for a melanoma study that aims to assess if specific phenotypic features, melanoma risk alleles, and environmental factors (eg, duty station location, occupation, amount of UV exposure) can be used to develop better screening models to identify individuals who are at risk for developing melanoma. Secondarily, the study aims to determine if recently developed multimarker diagnostic and prognostic assays for melanoma will prove useful in the diagnostic and prognostic assessment of melanocytic neoplasms in the military population. For this study, one of the authors (J.H.M) is utilizing DoDSR serum from 1700 retrospective cases of invasive melanoma and 1700 matched controls. Additionally, the Automated Central Tumor Registry and Department of Pathology and Area Laboratory Services databases are being used to obtain tissue from more than 300 melanoma cases and nevi controls.

Limitations of the Current System

Despite the impressive capabilities of the current system, there are some issues that limit its potential. One such limitation is associated with the way that the serum samples at the DoDSR are utilized. Through 2012, the DoDSR had 54,542,658 serum specimens available, of which only 228,610 (0.42%) had ever been accessed for study.⁸ With such a wealth of information and relative availability, why are the serum samples not being accessed more frequently for studies? The inherent nature of the DoDSR being a restricted facility and only accessible to DoD-affiliated investigators may contribute, which allows the DoDSR to fulfill its primary purpose of contributing to military-relevant investigations but at the same time limits the number and type of investigations that can be performed. One idea that has been proposed is allowing civilian investigator access to the DoDSR if it can be proven that the research is targeted toward military-relevant issues.⁸ However, the current AFHSC access guidelines would need revision and would require additional safeguards to ensure that military-protected health information is not compromised. Nonetheless, such a change may result in more extensive use of DoDSR resources in the future.

An ethical issue that needs to be addressed pertains to how the DoDSR permits use of human serum samples for research purposes without getting consent from the individuals being studied. The serum samples are collected as part of mandatory predeployment and postdeployment examinations for HIV screening of all military members. These individuals are not informed of potential use of their serum specimens for research purposes and no consent forms or opt-out options are provided. Although it is true that military members must comply with specific requirements pertaining to military readiness (eg, receiving appropriate vaccinations, drug testing, regular medical screening), it is debated whether they still retain the right as patients to refuse participating in research and clinical trials.¹⁰ The AFHSC does have several regulatory steps in place to ensure that military members’ samples are used in an appropriate manner, including requiring a DoD primary investigator, IRB review of every research proposal, and de-identification of samples. At a minimum, giving military members the ability to provide informed consent would ensure that the military system is adhering to evolving human research standards.

The current lack of biological specimens other than serum in the DoDSR is another limitation of the current system. Recent advances in molecular analyses are impacted by expanding -omics techniques, such as epigenomics, transcriptomics, and proteomics. The field of epigenomics is the study of reversible changes to DNA (eg, methylation) associated with specific disease states or following specific environmental exposures.^9,11 Transcriptomics, which analyzes messenger RNA transcript levels of expressed genes, and proteomics, which uses expression of proteins, are 2 techniques being used to develop biomarkers associated with specific diseases and environmental exposures.^9,11 Serum alone does not provide the high-quality nucleic acids needed for many of these studies to take place. Adding whole-blood specimens or blood spot samples of military service members to the DoDSR would allow researchers to use these techniques to investigate many new biomarkers associated with military-relevant diseases and exposures. These techniques also can be used in the expanding field of personalized medicine so that health care providers are able to tailor all phases of care, including diagnosis and treatment, to an individual’s genetic profile.

Conclusion

The history of research in military medicine has been built on achieving the primary goal of serving those men and women who put their lives in danger to protect this country. In an evolving environment of new technologies that have led to changes in service members’ injuries, exposures, and diseases, military medicine also must adapt. Resources such as the DoDSR and DMSS, which provide investigators with the unique ability to link epidemiological data with serum samples, have been invaluable contributors to this overall mission. As with any large system, there are always improvements that can be made. Improving access to the DoDSR serum samples, educating and obtaining consent from military service members to use their samples in research, and adding specimens to the DoDSR that can be used for -omics techniques are 3 changes that should be considered to maximize the potential of the military medical research system.

Advances in medical biotechnologies, data-gathering techniques, and -omics technologies have resulted in the broader understanding of disease pathology and treatment and have facilitated the individualization of health care plans to meet the unique needs of each patient. Military medicine often has been on the forefront of medical technology, disease understanding, and clinical care both on and off the battlefield, in large part due to the unique resources available in the military health care system. These resources allow investigators the ability to integrate vast amounts of epidemiologic data with an extensive biological sample database of its service members, which in the modern age has translated into advances in the understanding of melanoma and the treatment of scars.

History of Research in the Military

Starting in the 1950s, the US Department of Defense (DoD) started to collect serum samples of its service members for the purpose of research.¹ It was not until 1985 that the DoD implemented a long-term frozen storage system for serum samples obtained through mandatory screening for human immunodeficiency virus (HIV) in service members.² Subsequently, the Department of Defense Serum Repository (DoDSR) was officially established in 1989 as a central archive for the long-term storage of serum obtained from active-duty and reserve service members in the US Navy, Army, and Marines.^2,3 In the mid-1990s, the DoDSR expanded its capabilities to include the storage of serum samples from all military members, including the US Air Force, obtained predeployment and postdeployment.^3,4 At that time, a records-keeping system was established, now known as the Defense Medical Surveillance System (DMSS). The creation of the DMSS provided an extensive epidemiologic database that provided valuable information such as demographic data, service records, deployment data, reportable medical events, exposure history, and vaccination records, which could be linked to the serum samples of each service member.^2-4 Since 2008, the responsibilities of maintaining the DoDSR and the DMSS were transferred to the Armed Forces Health Surveillance Center (AFHSC).⁵

There have been several other databases created over the years that provide additional support and resources to military investigators. The Automated Central Tumor Registry and Department of Pathology and Area Laboratory Services both help investigators to track the incidence of specific cancers in the military population and provide them with pathologic specimens. Additionally, electronic medical records including the composite health care system and the Armed Forces Health Longitudinal Technology Application supplemented with insurance claims data accessible from the Military Health System Management and Reporting Tool (M2) database have made it possible to track patient data.

Utilization of Military Research Resources

Today, the DoDSR is a secure facility that maintains more than 56 million serum specimens from more than 11 million individuals in –30°C freezers, making it one of the largest repositories in the world.^3,6 Each serum sample is linked with an individual’s DMSS record, providing a way for investigators to study how external factors such as deployment history, occupation, and exposure history relate to an individual’s unique genetic and physiological makeup. Furthermore, these data can be used for seroepidemiologic investigations that contribute to all facets of clinical care. The AFHSC routinely publishes findings related to notifiable diseases, disease outbreaks, and disease trends in a monthly report.⁷

There are strict guidelines in place that limit access to the DoDSR and service members’ data. Use of the repository for information directly related to a patient’s health care is one reason for access, such as analyzing serum for antibodies and seroconversion to assist in the diagnosis of a disease such as HIV. Another reason would be to obtain information needed for criminal investigations and prosecution. Typically, these types of requests require a judge-issued court order and approval by the Assistant Secretary of Defense for Health Affairs.⁴ The DoDSR also is used to study force health protection issues, such as infectious disease incidence and disease prevalence in the military population.

Obtaining access to the DoDSR and service members’ data for research purposes requires that the principal investigator be a DoD employee. Each research proposal is reviewed by members of the AFHSC to determine if the DoDSR is able to meet the demands of the project, including having the appropriate number of serum samples and supporting epidemiologic data available. The AFHSC provides a letter of support if it deems the project to be in line with its current resources and capabilities. Each research proposal is then sent to an institutional review board (IRB) to determine if the study is exempt or needs to go through a full IRB review process. A study might be exempt if the investigators are not obtaining data through interaction with living individuals or not having access to any identifiable protected health information associated with the samples.⁶ Regardless of whether the study is exempt or not exempt, the AFHSC will de-identify each sample before releasing the samples to the investigators by using a coding system to shield the patient’s identity from the investigator.

Resources within the military medical research system provide investigators with access to an extensive biorepository of serum and linked epidemiological data. Samples from the DoDSR have been used in no less than 75 peer-reviewed publications since 1985.^8,9 Several of these studies have been influential in expanding knowledge about conditions seen more commonly in the military population such as stress fractures, traumatic brain injuries, posttraumatic stress disorder, and suicide.⁸ Additionally, DoDSR samples have been used to form military vaccination policies and track both infectious and noninfectious conditions in the military; for example, during the H1N1 influenza virus outbreak of 2009, AFHSC was essential in helping to limit the spread of the virus within the military community by using its data and collaborating with groups such as the Centers for Disease Control and Prevention to develop a plan for disease surveillance and control.⁵

Several military research resources are currently being used for a melanoma study that aims to assess if specific phenotypic features, melanoma risk alleles, and environmental factors (eg, duty station location, occupation, amount of UV exposure) can be used to develop better screening models to identify individuals who are at risk for developing melanoma. Secondarily, the study aims to determine if recently developed multimarker diagnostic and prognostic assays for melanoma will prove useful in the diagnostic and prognostic assessment of melanocytic neoplasms in the military population. For this study, one of the authors (J.H.M) is utilizing DoDSR serum from 1700 retrospective cases of invasive melanoma and 1700 matched controls. Additionally, the Automated Central Tumor Registry and Department of Pathology and Area Laboratory Services databases are being used to obtain tissue from more than 300 melanoma cases and nevi controls.

Limitations of the Current System

Despite the impressive capabilities of the current system, there are some issues that limit its potential. One such limitation is associated with the way that the serum samples at the DoDSR are utilized. Through 2012, the DoDSR had 54,542,658 serum specimens available, of which only 228,610 (0.42%) had ever been accessed for study.⁸ With such a wealth of information and relative availability, why are the serum samples not being accessed more frequently for studies? The inherent nature of the DoDSR being a restricted facility and only accessible to DoD-affiliated investigators may contribute, which allows the DoDSR to fulfill its primary purpose of contributing to military-relevant investigations but at the same time limits the number and type of investigations that can be performed. One idea that has been proposed is allowing civilian investigator access to the DoDSR if it can be proven that the research is targeted toward military-relevant issues.⁸ However, the current AFHSC access guidelines would need revision and would require additional safeguards to ensure that military-protected health information is not compromised. Nonetheless, such a change may result in more extensive use of DoDSR resources in the future.

An ethical issue that needs to be addressed pertains to how the DoDSR permits use of human serum samples for research purposes without getting consent from the individuals being studied. The serum samples are collected as part of mandatory predeployment and postdeployment examinations for HIV screening of all military members. These individuals are not informed of potential use of their serum specimens for research purposes and no consent forms or opt-out options are provided. Although it is true that military members must comply with specific requirements pertaining to military readiness (eg, receiving appropriate vaccinations, drug testing, regular medical screening), it is debated whether they still retain the right as patients to refuse participating in research and clinical trials.¹⁰ The AFHSC does have several regulatory steps in place to ensure that military members’ samples are used in an appropriate manner, including requiring a DoD primary investigator, IRB review of every research proposal, and de-identification of samples. At a minimum, giving military members the ability to provide informed consent would ensure that the military system is adhering to evolving human research standards.

The current lack of biological specimens other than serum in the DoDSR is another limitation of the current system. Recent advances in molecular analyses are impacted by expanding -omics techniques, such as epigenomics, transcriptomics, and proteomics. The field of epigenomics is the study of reversible changes to DNA (eg, methylation) associated with specific disease states or following specific environmental exposures.^9,11 Transcriptomics, which analyzes messenger RNA transcript levels of expressed genes, and proteomics, which uses expression of proteins, are 2 techniques being used to develop biomarkers associated with specific diseases and environmental exposures.^9,11 Serum alone does not provide the high-quality nucleic acids needed for many of these studies to take place. Adding whole-blood specimens or blood spot samples of military service members to the DoDSR would allow researchers to use these techniques to investigate many new biomarkers associated with military-relevant diseases and exposures. These techniques also can be used in the expanding field of personalized medicine so that health care providers are able to tailor all phases of care, including diagnosis and treatment, to an individual’s genetic profile.

Conclusion

The history of research in military medicine has been built on achieving the primary goal of serving those men and women who put their lives in danger to protect this country. In an evolving environment of new technologies that have led to changes in service members’ injuries, exposures, and diseases, military medicine also must adapt. Resources such as the DoDSR and DMSS, which provide investigators with the unique ability to link epidemiological data with serum samples, have been invaluable contributors to this overall mission. As with any large system, there are always improvements that can be made. Improving access to the DoDSR serum samples, educating and obtaining consent from military service members to use their samples in research, and adding specimens to the DoDSR that can be used for -omics techniques are 3 changes that should be considered to maximize the potential of the military medical research system.

Advances in medical biotechnologies, data-gathering techniques, and -omics technologies have resulted in the broader understanding of disease pathology and treatment and have facilitated the individualization of health care plans to meet the unique needs of each patient. Military medicine often has been on the forefront of medical technology, disease understanding, and clinical care both on and off the battlefield, in large part due to the unique resources available in the military health care system. These resources allow investigators the ability to integrate vast amounts of epidemiologic data with an extensive biological sample database of its service members, which in the modern age has translated into advances in the understanding of melanoma and the treatment of scars.

History of Research in the Military

Starting in the 1950s, the US Department of Defense (DoD) started to collect serum samples of its service members for the purpose of research.¹ It was not until 1985 that the DoD implemented a long-term frozen storage system for serum samples obtained through mandatory screening for human immunodeficiency virus (HIV) in service members.² Subsequently, the Department of Defense Serum Repository (DoDSR) was officially established in 1989 as a central archive for the long-term storage of serum obtained from active-duty and reserve service members in the US Navy, Army, and Marines.^2,3 In the mid-1990s, the DoDSR expanded its capabilities to include the storage of serum samples from all military members, including the US Air Force, obtained predeployment and postdeployment.^3,4 At that time, a records-keeping system was established, now known as the Defense Medical Surveillance System (DMSS). The creation of the DMSS provided an extensive epidemiologic database that provided valuable information such as demographic data, service records, deployment data, reportable medical events, exposure history, and vaccination records, which could be linked to the serum samples of each service member.^2-4 Since 2008, the responsibilities of maintaining the DoDSR and the DMSS were transferred to the Armed Forces Health Surveillance Center (AFHSC).⁵

There have been several other databases created over the years that provide additional support and resources to military investigators. The Automated Central Tumor Registry and Department of Pathology and Area Laboratory Services both help investigators to track the incidence of specific cancers in the military population and provide them with pathologic specimens. Additionally, electronic medical records including the composite health care system and the Armed Forces Health Longitudinal Technology Application supplemented with insurance claims data accessible from the Military Health System Management and Reporting Tool (M2) database have made it possible to track patient data.

Utilization of Military Research Resources

Today, the DoDSR is a secure facility that maintains more than 56 million serum specimens from more than 11 million individuals in –30°C freezers, making it one of the largest repositories in the world.^3,6 Each serum sample is linked with an individual’s DMSS record, providing a way for investigators to study how external factors such as deployment history, occupation, and exposure history relate to an individual’s unique genetic and physiological makeup. Furthermore, these data can be used for seroepidemiologic investigations that contribute to all facets of clinical care. The AFHSC routinely publishes findings related to notifiable diseases, disease outbreaks, and disease trends in a monthly report.⁷

There are strict guidelines in place that limit access to the DoDSR and service members’ data. Use of the repository for information directly related to a patient’s health care is one reason for access, such as analyzing serum for antibodies and seroconversion to assist in the diagnosis of a disease such as HIV. Another reason would be to obtain information needed for criminal investigations and prosecution. Typically, these types of requests require a judge-issued court order and approval by the Assistant Secretary of Defense for Health Affairs.⁴ The DoDSR also is used to study force health protection issues, such as infectious disease incidence and disease prevalence in the military population.

Obtaining access to the DoDSR and service members’ data for research purposes requires that the principal investigator be a DoD employee. Each research proposal is reviewed by members of the AFHSC to determine if the DoDSR is able to meet the demands of the project, including having the appropriate number of serum samples and supporting epidemiologic data available. The AFHSC provides a letter of support if it deems the project to be in line with its current resources and capabilities. Each research proposal is then sent to an institutional review board (IRB) to determine if the study is exempt or needs to go through a full IRB review process. A study might be exempt if the investigators are not obtaining data through interaction with living individuals or not having access to any identifiable protected health information associated with the samples.⁶ Regardless of whether the study is exempt or not exempt, the AFHSC will de-identify each sample before releasing the samples to the investigators by using a coding system to shield the patient’s identity from the investigator.

Resources within the military medical research system provide investigators with access to an extensive biorepository of serum and linked epidemiological data. Samples from the DoDSR have been used in no less than 75 peer-reviewed publications since 1985.^8,9 Several of these studies have been influential in expanding knowledge about conditions seen more commonly in the military population such as stress fractures, traumatic brain injuries, posttraumatic stress disorder, and suicide.⁸ Additionally, DoDSR samples have been used to form military vaccination policies and track both infectious and noninfectious conditions in the military; for example, during the H1N1 influenza virus outbreak of 2009, AFHSC was essential in helping to limit the spread of the virus within the military community by using its data and collaborating with groups such as the Centers for Disease Control and Prevention to develop a plan for disease surveillance and control.⁵

Several military research resources are currently being used for a melanoma study that aims to assess if specific phenotypic features, melanoma risk alleles, and environmental factors (eg, duty station location, occupation, amount of UV exposure) can be used to develop better screening models to identify individuals who are at risk for developing melanoma. Secondarily, the study aims to determine if recently developed multimarker diagnostic and prognostic assays for melanoma will prove useful in the diagnostic and prognostic assessment of melanocytic neoplasms in the military population. For this study, one of the authors (J.H.M) is utilizing DoDSR serum from 1700 retrospective cases of invasive melanoma and 1700 matched controls. Additionally, the Automated Central Tumor Registry and Department of Pathology and Area Laboratory Services databases are being used to obtain tissue from more than 300 melanoma cases and nevi controls.

Limitations of the Current System

Despite the impressive capabilities of the current system, there are some issues that limit its potential. One such limitation is associated with the way that the serum samples at the DoDSR are utilized. Through 2012, the DoDSR had 54,542,658 serum specimens available, of which only 228,610 (0.42%) had ever been accessed for study.⁸ With such a wealth of information and relative availability, why are the serum samples not being accessed more frequently for studies? The inherent nature of the DoDSR being a restricted facility and only accessible to DoD-affiliated investigators may contribute, which allows the DoDSR to fulfill its primary purpose of contributing to military-relevant investigations but at the same time limits the number and type of investigations that can be performed. One idea that has been proposed is allowing civilian investigator access to the DoDSR if it can be proven that the research is targeted toward military-relevant issues.⁸ However, the current AFHSC access guidelines would need revision and would require additional safeguards to ensure that military-protected health information is not compromised. Nonetheless, such a change may result in more extensive use of DoDSR resources in the future.

An ethical issue that needs to be addressed pertains to how the DoDSR permits use of human serum samples for research purposes without getting consent from the individuals being studied. The serum samples are collected as part of mandatory predeployment and postdeployment examinations for HIV screening of all military members. These individuals are not informed of potential use of their serum specimens for research purposes and no consent forms or opt-out options are provided. Although it is true that military members must comply with specific requirements pertaining to military readiness (eg, receiving appropriate vaccinations, drug testing, regular medical screening), it is debated whether they still retain the right as patients to refuse participating in research and clinical trials.¹⁰ The AFHSC does have several regulatory steps in place to ensure that military members’ samples are used in an appropriate manner, including requiring a DoD primary investigator, IRB review of every research proposal, and de-identification of samples. At a minimum, giving military members the ability to provide informed consent would ensure that the military system is adhering to evolving human research standards.

The current lack of biological specimens other than serum in the DoDSR is another limitation of the current system. Recent advances in molecular analyses are impacted by expanding -omics techniques, such as epigenomics, transcriptomics, and proteomics. The field of epigenomics is the study of reversible changes to DNA (eg, methylation) associated with specific disease states or following specific environmental exposures.^9,11 Transcriptomics, which analyzes messenger RNA transcript levels of expressed genes, and proteomics, which uses expression of proteins, are 2 techniques being used to develop biomarkers associated with specific diseases and environmental exposures.^9,11 Serum alone does not provide the high-quality nucleic acids needed for many of these studies to take place. Adding whole-blood specimens or blood spot samples of military service members to the DoDSR would allow researchers to use these techniques to investigate many new biomarkers associated with military-relevant diseases and exposures. These techniques also can be used in the expanding field of personalized medicine so that health care providers are able to tailor all phases of care, including diagnosis and treatment, to an individual’s genetic profile.

Conclusion

The history of research in military medicine has been built on achieving the primary goal of serving those men and women who put their lives in danger to protect this country. In an evolving environment of new technologies that have led to changes in service members’ injuries, exposures, and diseases, military medicine also must adapt. Resources such as the DoDSR and DMSS, which provide investigators with the unique ability to link epidemiological data with serum samples, have been invaluable contributors to this overall mission. As with any large system, there are always improvements that can be made. Improving access to the DoDSR serum samples, educating and obtaining consent from military service members to use their samples in research, and adding specimens to the DoDSR that can be used for -omics techniques are 3 changes that should be considered to maximize the potential of the military medical research system.

Just as Charlie Brown looks forward to the coming of the Great Pumpkin each Halloween, those of us who dance in the minefields of payment policy await the publication of the Proposed Rule, more formally known as the “Revisions to Payment Policies under the Physician Fee Schedule and Other Revisions to Part B for CY 2017.”^1,2 You could read the entire tome—a mere 316 pages (excluding the hundreds of pages of granular supplement data discussed in the last few columns)—or simply read what I have outlined as the good, the bad, and the ugly for the Proposed Rule for 2017.

The Good

In 2017, dermatology will increase its share of the pie by 1% to $3.505 billion of a total $89.467 billion expected to be expended for physician services.¹ The effect on individual providers will vary by geographic location and practice mix. Half is from the 0.5% increase that has come to all physicians across the board as mandated by the Medicare Access and CHIP Reauthorization Act (MACRA).³

Current Procedural Terminology (CPT) codes for reflectance confocal microscopy (96931–96936) will have Centers for Medicare & Medicaid Services valuations beginning in 2017, and individuals performing this service should be able to report it and be paid for their efforts.¹ The values are below the American Medical Association/Specialty Society Relative Value Scale Update Committee (RUC) recommendations.

The Bad

Payment rates for 2017 will be based on a conversion factor of 35.7751,¹ a drop from the 2016 conversion factor of 35.8043. Cuts will be made for some specialties. Gastroenterology, nephrology, neurosurgery, radiology, urology, and radiation therapy centers will take a 1% hit; ophthalmology, pathology, and vascular surgery will take 2% cuts; and interventional radiology will lose 7%.¹ A special case within dermatology and pathology is a 15% cut to the technical component of slide preparation for CPT code 88305⁴ due to a redefinition of the valuation of eosin stains.² While the accuracy and precision of the value of these practice expense inputs can be debated, the government by definition makes the rules and involved specialties had an opportunity to appeal this change through the comment process that ended on September 6, 2016. The government can take comments into account, but substantial changes usually are not made from the Proposed Rule to the Final Rule, which usually arrives around the beginning of November; however, in an election year, the Final Rule can be a few weeks late.

The Ugly

The government will increase its unfunded mandates with the creation of new Medicare G codes (global services codes) that will allow the government to track the provision of postoperative care for all 010 and 090 global service periods (Table 1). The codes look mostly at time and do not clearly take into account the severity or complexity of the conditions being cared for and will be reported on claim forms as an unfunded mandate with more confusion and cost.¹ Because not all claim-paying intermediaries are likely to have these G codes smoothly set up in their systems, there will still be a cost to filing the claim. Unless changes occur in the Final Rule, which is unlikely, there will be no payment for the time and effort of submitting these claims. The goal of the US Government is to hone in on postoperative services and parse them down so they can cut payments wherever possible beginning in 2019.¹ Everyone wants to save money, from the consumer⁵ to the payer, and the ultimate payer is playing hardball. Additional validation efforts likely will lower physician fee-for-service payments further.

The US Government also is taking a shot at what they call “misvalued services” that have not had recent refinement within the RUC process.¹ The work list for 2017 includes a number of 000 global period codes where additional evaluation and management services are reported using modifier -25, which implies a substantial, separately identifiable cognitive service performed by the same physician on the day of a procedure above and beyond other services provided or beyond the usual preservice and postservice care associated with the procedure that was performed. Although codes such as biopsies (11100 and 11101) and premalignant destructions (17000–17004) have an adjustment built in and dermatologists who provide services on the same day are actually penalized for the multiple built-in reductions that are already additive, the government is concerned that 19% of the 000 global services were billed more than 50% of the time with an evaluation and management code with modifier -25. Eighty-three codes met the criteria for which the government believes it may be overpaying¹; the codes of interest to dermatology are shown in Table 2.¹

Final Thoughts

I end this column with an appeal to the dermatologists of America. Go to the American Academy of Dermatology Association Political Action Committee website (https://skinpac.org/), the home page for the only political action committee that represents the dermatology specialty, and consider making a donation. Emergency medicine physicians created the “Giving a Shift” campaign, which is a donation to their national political action committee of one shift’s earnings, and most of us could easily donate a half day’s income, as the only way to potentially change the increasingly onerous burdens on practitioners is through political action. As we say at RUC meetings, you can eat lunch or be lunch. The choice is yours.

Just as Charlie Brown looks forward to the coming of the Great Pumpkin each Halloween, those of us who dance in the minefields of payment policy await the publication of the Proposed Rule, more formally known as the “Revisions to Payment Policies under the Physician Fee Schedule and Other Revisions to Part B for CY 2017.”^1,2 You could read the entire tome—a mere 316 pages (excluding the hundreds of pages of granular supplement data discussed in the last few columns)—or simply read what I have outlined as the good, the bad, and the ugly for the Proposed Rule for 2017.

The Good

In 2017, dermatology will increase its share of the pie by 1% to $3.505 billion of a total $89.467 billion expected to be expended for physician services.¹ The effect on individual providers will vary by geographic location and practice mix. Half is from the 0.5% increase that has come to all physicians across the board as mandated by the Medicare Access and CHIP Reauthorization Act (MACRA).³

Current Procedural Terminology (CPT) codes for reflectance confocal microscopy (96931–96936) will have Centers for Medicare & Medicaid Services valuations beginning in 2017, and individuals performing this service should be able to report it and be paid for their efforts.¹ The values are below the American Medical Association/Specialty Society Relative Value Scale Update Committee (RUC) recommendations.

The Bad

Payment rates for 2017 will be based on a conversion factor of 35.7751,¹ a drop from the 2016 conversion factor of 35.8043. Cuts will be made for some specialties. Gastroenterology, nephrology, neurosurgery, radiology, urology, and radiation therapy centers will take a 1% hit; ophthalmology, pathology, and vascular surgery will take 2% cuts; and interventional radiology will lose 7%.¹ A special case within dermatology and pathology is a 15% cut to the technical component of slide preparation for CPT code 88305⁴ due to a redefinition of the valuation of eosin stains.² While the accuracy and precision of the value of these practice expense inputs can be debated, the government by definition makes the rules and involved specialties had an opportunity to appeal this change through the comment process that ended on September 6, 2016. The government can take comments into account, but substantial changes usually are not made from the Proposed Rule to the Final Rule, which usually arrives around the beginning of November; however, in an election year, the Final Rule can be a few weeks late.

The Ugly

The government will increase its unfunded mandates with the creation of new Medicare G codes (global services codes) that will allow the government to track the provision of postoperative care for all 010 and 090 global service periods (Table 1). The codes look mostly at time and do not clearly take into account the severity or complexity of the conditions being cared for and will be reported on claim forms as an unfunded mandate with more confusion and cost.¹ Because not all claim-paying intermediaries are likely to have these G codes smoothly set up in their systems, there will still be a cost to filing the claim. Unless changes occur in the Final Rule, which is unlikely, there will be no payment for the time and effort of submitting these claims. The goal of the US Government is to hone in on postoperative services and parse them down so they can cut payments wherever possible beginning in 2019.¹ Everyone wants to save money, from the consumer⁵ to the payer, and the ultimate payer is playing hardball. Additional validation efforts likely will lower physician fee-for-service payments further.

The US Government also is taking a shot at what they call “misvalued services” that have not had recent refinement within the RUC process.¹ The work list for 2017 includes a number of 000 global period codes where additional evaluation and management services are reported using modifier -25, which implies a substantial, separately identifiable cognitive service performed by the same physician on the day of a procedure above and beyond other services provided or beyond the usual preservice and postservice care associated with the procedure that was performed. Although codes such as biopsies (11100 and 11101) and premalignant destructions (17000–17004) have an adjustment built in and dermatologists who provide services on the same day are actually penalized for the multiple built-in reductions that are already additive, the government is concerned that 19% of the 000 global services were billed more than 50% of the time with an evaluation and management code with modifier -25. Eighty-three codes met the criteria for which the government believes it may be overpaying¹; the codes of interest to dermatology are shown in Table 2.¹

Final Thoughts

I end this column with an appeal to the dermatologists of America. Go to the American Academy of Dermatology Association Political Action Committee website (https://skinpac.org/), the home page for the only political action committee that represents the dermatology specialty, and consider making a donation. Emergency medicine physicians created the “Giving a Shift” campaign, which is a donation to their national political action committee of one shift’s earnings, and most of us could easily donate a half day’s income, as the only way to potentially change the increasingly onerous burdens on practitioners is through political action. As we say at RUC meetings, you can eat lunch or be lunch. The choice is yours.

Just as Charlie Brown looks forward to the coming of the Great Pumpkin each Halloween, those of us who dance in the minefields of payment policy await the publication of the Proposed Rule, more formally known as the “Revisions to Payment Policies under the Physician Fee Schedule and Other Revisions to Part B for CY 2017.”^1,2 You could read the entire tome—a mere 316 pages (excluding the hundreds of pages of granular supplement data discussed in the last few columns)—or simply read what I have outlined as the good, the bad, and the ugly for the Proposed Rule for 2017.

The Good

In 2017, dermatology will increase its share of the pie by 1% to $3.505 billion of a total $89.467 billion expected to be expended for physician services.¹ The effect on individual providers will vary by geographic location and practice mix. Half is from the 0.5% increase that has come to all physicians across the board as mandated by the Medicare Access and CHIP Reauthorization Act (MACRA).³

Current Procedural Terminology (CPT) codes for reflectance confocal microscopy (96931–96936) will have Centers for Medicare & Medicaid Services valuations beginning in 2017, and individuals performing this service should be able to report it and be paid for their efforts.¹ The values are below the American Medical Association/Specialty Society Relative Value Scale Update Committee (RUC) recommendations.

The Bad

Payment rates for 2017 will be based on a conversion factor of 35.7751,¹ a drop from the 2016 conversion factor of 35.8043. Cuts will be made for some specialties. Gastroenterology, nephrology, neurosurgery, radiology, urology, and radiation therapy centers will take a 1% hit; ophthalmology, pathology, and vascular surgery will take 2% cuts; and interventional radiology will lose 7%.¹ A special case within dermatology and pathology is a 15% cut to the technical component of slide preparation for CPT code 88305⁴ due to a redefinition of the valuation of eosin stains.² While the accuracy and precision of the value of these practice expense inputs can be debated, the government by definition makes the rules and involved specialties had an opportunity to appeal this change through the comment process that ended on September 6, 2016. The government can take comments into account, but substantial changes usually are not made from the Proposed Rule to the Final Rule, which usually arrives around the beginning of November; however, in an election year, the Final Rule can be a few weeks late.

The Ugly

The government will increase its unfunded mandates with the creation of new Medicare G codes (global services codes) that will allow the government to track the provision of postoperative care for all 010 and 090 global service periods (Table 1). The codes look mostly at time and do not clearly take into account the severity or complexity of the conditions being cared for and will be reported on claim forms as an unfunded mandate with more confusion and cost.¹ Because not all claim-paying intermediaries are likely to have these G codes smoothly set up in their systems, there will still be a cost to filing the claim. Unless changes occur in the Final Rule, which is unlikely, there will be no payment for the time and effort of submitting these claims. The goal of the US Government is to hone in on postoperative services and parse them down so they can cut payments wherever possible beginning in 2019.¹ Everyone wants to save money, from the consumer⁵ to the payer, and the ultimate payer is playing hardball. Additional validation efforts likely will lower physician fee-for-service payments further.

The US Government also is taking a shot at what they call “misvalued services” that have not had recent refinement within the RUC process.¹ The work list for 2017 includes a number of 000 global period codes where additional evaluation and management services are reported using modifier -25, which implies a substantial, separately identifiable cognitive service performed by the same physician on the day of a procedure above and beyond other services provided or beyond the usual preservice and postservice care associated with the procedure that was performed. Although codes such as biopsies (11100 and 11101) and premalignant destructions (17000–17004) have an adjustment built in and dermatologists who provide services on the same day are actually penalized for the multiple built-in reductions that are already additive, the government is concerned that 19% of the 000 global services were billed more than 50% of the time with an evaluation and management code with modifier -25. Eighty-three codes met the criteria for which the government believes it may be overpaying¹; the codes of interest to dermatology are shown in Table 2.¹

Final Thoughts

I end this column with an appeal to the dermatologists of America. Go to the American Academy of Dermatology Association Political Action Committee website (https://skinpac.org/), the home page for the only political action committee that represents the dermatology specialty, and consider making a donation. Emergency medicine physicians created the “Giving a Shift” campaign, which is a donation to their national political action committee of one shift’s earnings, and most of us could easily donate a half day’s income, as the only way to potentially change the increasingly onerous burdens on practitioners is through political action. As we say at RUC meetings, you can eat lunch or be lunch. The choice is yours.

Carmex Comfort Care

Carma Labs Inc introduces Carmex Comfort Care lip balm, a natural lip care product formulated with colloidal oatmeal and cold-pressed fruit oil to deliver soothing, long-lasting moisture and hydration. Colloidal oatmeal also possesses antioxidant and anti-inflammatory properties that benefit sensitive drug skin, especially on the lips. For more information, visit www.mycarmex.com.

Erelzi

Sandoz Inc, a Novartis Division, announces US Food and Drug Administration approval of Erelzi (etanercept-szzs) for all indications included in the reference product label: rheumatoid arthritis, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, and polyarticular juvenile idiopathic arthritis. Erelzi is the second approved biosimilar from Sandoz. For more information, visit www.erelzi.com.

Loprox Cream

Medimetriks Pharmaceuticals, Inc, announces the launch of Loprox (ciclopirox) Cream 0.77% and the Loprox Cream Kit. Loprox Cream is a broad-spectrum therapy that treats 5 different skin infections from 6 different pathogens. It is indicated for the topical treatment of tinea pedis, tinea cruris, and tinea corporis due to Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, and Microsporum canis; candidiasis due to Candia albicans; and tinea (pityriasis) versicolor due to Malassezia furfur. Loprox Cream works quickly, usually within the first week (2 weeks for tinea versicolor), providing patients needed relief of pruritus and other symptoms. The Loprox Cream Kit includes Loprox Cream and Rehyla Hair + Body Cleanser for patient convenience. The cleanser hydrates and conditions and is gentle for daily use on the scalp and body. For more information, visit www.medimetriks.com.

If you would like your product included in Product News, please email a press release to the Editorial Office at [email protected].

Carmex Comfort Care

Carma Labs Inc introduces Carmex Comfort Care lip balm, a natural lip care product formulated with colloidal oatmeal and cold-pressed fruit oil to deliver soothing, long-lasting moisture and hydration. Colloidal oatmeal also possesses antioxidant and anti-inflammatory properties that benefit sensitive drug skin, especially on the lips. For more information, visit www.mycarmex.com.

Erelzi

Sandoz Inc, a Novartis Division, announces US Food and Drug Administration approval of Erelzi (etanercept-szzs) for all indications included in the reference product label: rheumatoid arthritis, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, and polyarticular juvenile idiopathic arthritis. Erelzi is the second approved biosimilar from Sandoz. For more information, visit www.erelzi.com.

Loprox Cream

Medimetriks Pharmaceuticals, Inc, announces the launch of Loprox (ciclopirox) Cream 0.77% and the Loprox Cream Kit. Loprox Cream is a broad-spectrum therapy that treats 5 different skin infections from 6 different pathogens. It is indicated for the topical treatment of tinea pedis, tinea cruris, and tinea corporis due to Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, and Microsporum canis; candidiasis due to Candia albicans; and tinea (pityriasis) versicolor due to Malassezia furfur. Loprox Cream works quickly, usually within the first week (2 weeks for tinea versicolor), providing patients needed relief of pruritus and other symptoms. The Loprox Cream Kit includes Loprox Cream and Rehyla Hair + Body Cleanser for patient convenience. The cleanser hydrates and conditions and is gentle for daily use on the scalp and body. For more information, visit www.medimetriks.com.

If you would like your product included in Product News, please email a press release to the Editorial Office at [email protected].

Carmex Comfort Care

Carma Labs Inc introduces Carmex Comfort Care lip balm, a natural lip care product formulated with colloidal oatmeal and cold-pressed fruit oil to deliver soothing, long-lasting moisture and hydration. Colloidal oatmeal also possesses antioxidant and anti-inflammatory properties that benefit sensitive drug skin, especially on the lips. For more information, visit www.mycarmex.com.

Erelzi

Sandoz Inc, a Novartis Division, announces US Food and Drug Administration approval of Erelzi (etanercept-szzs) for all indications included in the reference product label: rheumatoid arthritis, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, and polyarticular juvenile idiopathic arthritis. Erelzi is the second approved biosimilar from Sandoz. For more information, visit www.erelzi.com.

Loprox Cream

Medimetriks Pharmaceuticals, Inc, announces the launch of Loprox (ciclopirox) Cream 0.77% and the Loprox Cream Kit. Loprox Cream is a broad-spectrum therapy that treats 5 different skin infections from 6 different pathogens. It is indicated for the topical treatment of tinea pedis, tinea cruris, and tinea corporis due to Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, and Microsporum canis; candidiasis due to Candia albicans; and tinea (pityriasis) versicolor due to Malassezia furfur. Loprox Cream works quickly, usually within the first week (2 weeks for tinea versicolor), providing patients needed relief of pruritus and other symptoms. The Loprox Cream Kit includes Loprox Cream and Rehyla Hair + Body Cleanser for patient convenience. The cleanser hydrates and conditions and is gentle for daily use on the scalp and body. For more information, visit www.medimetriks.com.

If you would like your product included in Product News, please email a press release to the Editorial Office at [email protected].

When my youngest daughter returns home from acting or dancing rehearsals, she talks about “notes” that she or the company received that day. Discussing them with her, I appreciate that giving notes to performers after rehearsal or even after a show is standard theater practice. The notes may be from the assistant stage director commenting on lines that were missed, mangled, or perfected. They also could be from the director concerning stage position or behaviors, or they may be about character development or a clarification about the emotions in a particular scene. They are written out as specific references to a certain line or segment of the script. Some directors write them on sticky memos so that they can actually be added to the actor’s script. Others keep their notes on index cards that can be sorted and handed out to the designated performer. My daughter works hard during the first part of the rehearsal process to get as few notes as possible, but at the end of the rehearsal process or during the run of the show, she likes getting notes as a reflection of how she is being perceived and to facilitate fine-tuning her performance.

Giving written notes in our offices to our colleagues, trainees, and staff after a day’s work is not likely to be productive; however, there are parts of this process that dermatologists can utilize. The notes give feedback that is timely and specific. They can be given to individuals or to the entire troupe. I also noticed that my daughter appeared to have a positive relationship with the note givers and looked for their feedback to improve her performance. When residents are on a procedural rotation with me, I endeavor to give them feedback every day about some part of their surgical technique to help them finesse their skills. I am not, however, as rigorous about giving feedback concerning other aspects of the practice, and so this editorial serves the purpose of reminding me that giving feedback is an important skill that we can and should use on a daily basis.

There are many guides for giving feedback. The Center for Creative Leadership developed a feedback technique called Situation-Behavior-Impact (S-B-I).¹ Similar to performance notes, it is simple, direct, and timely. Step 1: Capture the situation (S). Step 2: Describe the behavior (B). Step 3: Deliver the impact (I). For example, I have given the following feedback to many fellows when they are working with the resident: (S) “This morning when you two were finishing the repair, (B) you were talking about the lack of efficiency of the clinic in another hospital. (I) It made me uncomfortable because I believe the patient is the center of attention, and yet this was not a conversation that included him. I also worried that he would become nervous or anxious to hear about problems in a medical facility.” Another conversation could go: (S) “This morning with the patient with the eyelid tumor, (B) you told the patient that you would send the eye surgeon a photo so she could be prepared for the repair, and (I) I noticed the patient’s hands immediately relaxed.”

These are straightforward examples. There are more complicated situations that seem to require longer analysis; however, if we acquire the habit of immediate and specific feedback, there will be less need for more difficult conversations. Situation-Behavior-Impact is about behavior; it is not judgmental of the person, and it leaves room for the recipient to think about what happened without being defensive and to take action to create productive behaviors and improve performance. The Center for Creative Leadership recommends that feedback be framed as an observation, which further diminishes the development of a defensive rejection of the information.¹

Feedback is such an important loop for all of us professionally and personally because it is the mechanism that gives us the opportunity to improve our performance, so why don’t we always hear it in a constructive thought-provoking way? Stone and Heen² point out 3 triggers that escalate rejection of feedback: truth, relationship, and identity. They also can be described as immediate reactions: “You are wrong about your assessment,” “I don’t like you anyway,” and “You’re messing with who I am.” For those of you who want to up your game in any of your professional or personal arenas, Thanks for the Feedback: The Science and Art of Receiving Feedback Well² will open you up to seek out and take in feedback. Feedback-seeking behavior has been linked to higher job satisfaction, greater creativity on the job, and faster adaptation to change, while negative feedback has been linked to improved job performance.³ Interestingly, it also helps in our personal lives; a husband’s openness to influence and input from his spouse is a key predictor of marital health and stability^.4

In an effort to decrease resistance to hearing feedback, there are proponents of the sandwich technique in which a positive comment is made, then the negative feedback is given, followed by another positive comment. In my experience, this technique does not work. First, you have to give some thought to the appropriate items to bring to the discussion, so the conversation might be delayed long enough to obscure the memory of the details involved in the situations. Second, if you employ it often, the receiver tenses up with the first positive comment, knowing a negative comment will ensue, and so he/she is primed to reject the feedback before it is even offered. Finally, it confuses the priorities for the conversation. However, working over time to give more positive feedback than negative feedback (an average of 4–5 to 1) allows for the development of trust and mutual respect and quiets the urge to immediately reject the negative messages. In my experience, positive feedback is especially effective in creating engagement as well as validating and promoting desirable behaviors. Physicians may have to work deliberately to offer positive feedback because it is more natural for us to diagnose problems than to identify good health.

What impresses me most about the theater culture surrounding notes is that giving and receiving feedback is an expected element of the artistic process. As practitioners, wouldn’t we as well as our patients benefit if the culture of medicine also expected that we were giving each other feedback on a daily basis?

When my youngest daughter returns home from acting or dancing rehearsals, she talks about “notes” that she or the company received that day. Discussing them with her, I appreciate that giving notes to performers after rehearsal or even after a show is standard theater practice. The notes may be from the assistant stage director commenting on lines that were missed, mangled, or perfected. They also could be from the director concerning stage position or behaviors, or they may be about character development or a clarification about the emotions in a particular scene. They are written out as specific references to a certain line or segment of the script. Some directors write them on sticky memos so that they can actually be added to the actor’s script. Others keep their notes on index cards that can be sorted and handed out to the designated performer. My daughter works hard during the first part of the rehearsal process to get as few notes as possible, but at the end of the rehearsal process or during the run of the show, she likes getting notes as a reflection of how she is being perceived and to facilitate fine-tuning her performance.

Giving written notes in our offices to our colleagues, trainees, and staff after a day’s work is not likely to be productive; however, there are parts of this process that dermatologists can utilize. The notes give feedback that is timely and specific. They can be given to individuals or to the entire troupe. I also noticed that my daughter appeared to have a positive relationship with the note givers and looked for their feedback to improve her performance. When residents are on a procedural rotation with me, I endeavor to give them feedback every day about some part of their surgical technique to help them finesse their skills. I am not, however, as rigorous about giving feedback concerning other aspects of the practice, and so this editorial serves the purpose of reminding me that giving feedback is an important skill that we can and should use on a daily basis.

There are many guides for giving feedback. The Center for Creative Leadership developed a feedback technique called Situation-Behavior-Impact (S-B-I).¹ Similar to performance notes, it is simple, direct, and timely. Step 1: Capture the situation (S). Step 2: Describe the behavior (B). Step 3: Deliver the impact (I). For example, I have given the following feedback to many fellows when they are working with the resident: (S) “This morning when you two were finishing the repair, (B) you were talking about the lack of efficiency of the clinic in another hospital. (I) It made me uncomfortable because I believe the patient is the center of attention, and yet this was not a conversation that included him. I also worried that he would become nervous or anxious to hear about problems in a medical facility.” Another conversation could go: (S) “This morning with the patient with the eyelid tumor, (B) you told the patient that you would send the eye surgeon a photo so she could be prepared for the repair, and (I) I noticed the patient’s hands immediately relaxed.”

These are straightforward examples. There are more complicated situations that seem to require longer analysis; however, if we acquire the habit of immediate and specific feedback, there will be less need for more difficult conversations. Situation-Behavior-Impact is about behavior; it is not judgmental of the person, and it leaves room for the recipient to think about what happened without being defensive and to take action to create productive behaviors and improve performance. The Center for Creative Leadership recommends that feedback be framed as an observation, which further diminishes the development of a defensive rejection of the information.¹

Feedback is such an important loop for all of us professionally and personally because it is the mechanism that gives us the opportunity to improve our performance, so why don’t we always hear it in a constructive thought-provoking way? Stone and Heen² point out 3 triggers that escalate rejection of feedback: truth, relationship, and identity. They also can be described as immediate reactions: “You are wrong about your assessment,” “I don’t like you anyway,” and “You’re messing with who I am.” For those of you who want to up your game in any of your professional or personal arenas, Thanks for the Feedback: The Science and Art of Receiving Feedback Well² will open you up to seek out and take in feedback. Feedback-seeking behavior has been linked to higher job satisfaction, greater creativity on the job, and faster adaptation to change, while negative feedback has been linked to improved job performance.³ Interestingly, it also helps in our personal lives; a husband’s openness to influence and input from his spouse is a key predictor of marital health and stability^.4

In an effort to decrease resistance to hearing feedback, there are proponents of the sandwich technique in which a positive comment is made, then the negative feedback is given, followed by another positive comment. In my experience, this technique does not work. First, you have to give some thought to the appropriate items to bring to the discussion, so the conversation might be delayed long enough to obscure the memory of the details involved in the situations. Second, if you employ it often, the receiver tenses up with the first positive comment, knowing a negative comment will ensue, and so he/she is primed to reject the feedback before it is even offered. Finally, it confuses the priorities for the conversation. However, working over time to give more positive feedback than negative feedback (an average of 4–5 to 1) allows for the development of trust and mutual respect and quiets the urge to immediately reject the negative messages. In my experience, positive feedback is especially effective in creating engagement as well as validating and promoting desirable behaviors. Physicians may have to work deliberately to offer positive feedback because it is more natural for us to diagnose problems than to identify good health.

What impresses me most about the theater culture surrounding notes is that giving and receiving feedback is an expected element of the artistic process. As practitioners, wouldn’t we as well as our patients benefit if the culture of medicine also expected that we were giving each other feedback on a daily basis?

When my youngest daughter returns home from acting or dancing rehearsals, she talks about “notes” that she or the company received that day. Discussing them with her, I appreciate that giving notes to performers after rehearsal or even after a show is standard theater practice. The notes may be from the assistant stage director commenting on lines that were missed, mangled, or perfected. They also could be from the director concerning stage position or behaviors, or they may be about character development or a clarification about the emotions in a particular scene. They are written out as specific references to a certain line or segment of the script. Some directors write them on sticky memos so that they can actually be added to the actor’s script. Others keep their notes on index cards that can be sorted and handed out to the designated performer. My daughter works hard during the first part of the rehearsal process to get as few notes as possible, but at the end of the rehearsal process or during the run of the show, she likes getting notes as a reflection of how she is being perceived and to facilitate fine-tuning her performance.

Giving written notes in our offices to our colleagues, trainees, and staff after a day’s work is not likely to be productive; however, there are parts of this process that dermatologists can utilize. The notes give feedback that is timely and specific. They can be given to individuals or to the entire troupe. I also noticed that my daughter appeared to have a positive relationship with the note givers and looked for their feedback to improve her performance. When residents are on a procedural rotation with me, I endeavor to give them feedback every day about some part of their surgical technique to help them finesse their skills. I am not, however, as rigorous about giving feedback concerning other aspects of the practice, and so this editorial serves the purpose of reminding me that giving feedback is an important skill that we can and should use on a daily basis.

There are many guides for giving feedback. The Center for Creative Leadership developed a feedback technique called Situation-Behavior-Impact (S-B-I).¹ Similar to performance notes, it is simple, direct, and timely. Step 1: Capture the situation (S). Step 2: Describe the behavior (B). Step 3: Deliver the impact (I). For example, I have given the following feedback to many fellows when they are working with the resident: (S) “This morning when you two were finishing the repair, (B) you were talking about the lack of efficiency of the clinic in another hospital. (I) It made me uncomfortable because I believe the patient is the center of attention, and yet this was not a conversation that included him. I also worried that he would become nervous or anxious to hear about problems in a medical facility.” Another conversation could go: (S) “This morning with the patient with the eyelid tumor, (B) you told the patient that you would send the eye surgeon a photo so she could be prepared for the repair, and (I) I noticed the patient’s hands immediately relaxed.”

These are straightforward examples. There are more complicated situations that seem to require longer analysis; however, if we acquire the habit of immediate and specific feedback, there will be less need for more difficult conversations. Situation-Behavior-Impact is about behavior; it is not judgmental of the person, and it leaves room for the recipient to think about what happened without being defensive and to take action to create productive behaviors and improve performance. The Center for Creative Leadership recommends that feedback be framed as an observation, which further diminishes the development of a defensive rejection of the information.¹

Feedback is such an important loop for all of us professionally and personally because it is the mechanism that gives us the opportunity to improve our performance, so why don’t we always hear it in a constructive thought-provoking way? Stone and Heen² point out 3 triggers that escalate rejection of feedback: truth, relationship, and identity. They also can be described as immediate reactions: “You are wrong about your assessment,” “I don’t like you anyway,” and “You’re messing with who I am.” For those of you who want to up your game in any of your professional or personal arenas, Thanks for the Feedback: The Science and Art of Receiving Feedback Well² will open you up to seek out and take in feedback. Feedback-seeking behavior has been linked to higher job satisfaction, greater creativity on the job, and faster adaptation to change, while negative feedback has been linked to improved job performance.³ Interestingly, it also helps in our personal lives; a husband’s openness to influence and input from his spouse is a key predictor of marital health and stability^.4

In an effort to decrease resistance to hearing feedback, there are proponents of the sandwich technique in which a positive comment is made, then the negative feedback is given, followed by another positive comment. In my experience, this technique does not work. First, you have to give some thought to the appropriate items to bring to the discussion, so the conversation might be delayed long enough to obscure the memory of the details involved in the situations. Second, if you employ it often, the receiver tenses up with the first positive comment, knowing a negative comment will ensue, and so he/she is primed to reject the feedback before it is even offered. Finally, it confuses the priorities for the conversation. However, working over time to give more positive feedback than negative feedback (an average of 4–5 to 1) allows for the development of trust and mutual respect and quiets the urge to immediately reject the negative messages. In my experience, positive feedback is especially effective in creating engagement as well as validating and promoting desirable behaviors. Physicians may have to work deliberately to offer positive feedback because it is more natural for us to diagnose problems than to identify good health.

What impresses me most about the theater culture surrounding notes is that giving and receiving feedback is an expected element of the artistic process. As practitioners, wouldn’t we as well as our patients benefit if the culture of medicine also expected that we were giving each other feedback on a daily basis?