Epiduo Forte Gel

Galderma Laboratories, LP, announces US Food and Drug Administration approval of antibiotic-free Epiduo Forte (adapalene 0.3% and benzoyl peroxide 2.5%) Gel for the once-daily topical treatment of acne vulgaris. Epiduo Forte Gel contains a high concentration of adapalene, which works to unclog blocked pores and inhibits the release of proinflammatory mediators. Benzoyl peroxide offers antimicrobial properties. Epiduo Forte Gel can be considered for long-term use in patients with moderate to severe acne. The formulation is offered in a pump to provide convenient once-daily dosing. Epiduo Forte Gel will be available by prescription in early September 2015. For more information, visit www.galdermausa.com.

Odomzo

Novartis Pharmaceuticals Corporation obtains US Food and Drug Administration approval of Odomzo (sonidegib) 200-mg capsules for the treatment of adult patients with locally advanced basal cell carcinoma that has recurred following surgery or radiation therapy, or those who are not candidates for surgery or radiation therapy. Odomzo is an oral selective smoothened (SMO) inhibitor. SMO is a molecule that regulates the hedgehog signaling pathway, which plays a critical role in stem cell maintenance and tissue repair as well as in advanced basal cell carcinoma. For more information, visit www.novartis.com.

Physical Matte UV Defense SPF 50

SkinCeuticals introduces Physical Matte UV Defense SPF 50 sunscreen. This 100% mineral sunscreen is formulated with oil-absorbing powders to help minimize the appearance of sweat and oil to ensure a long-lasting matte finish while also providing broad-spectrum UVA/UVB protection. Physical Matte UV DefenseSPF 50 sunscreen is formulated for those with normal, combination, or oily skin with an uneven texture that is prone to shine. The mousse texture enhances application. It can be used alone or under makeup. For more information, visit www.skinceuticals.com.

Silagen Scar Refinement System

NewMedical Technology, Inc, introduces the Silagen Scar Refinement System, a line of 100% medical-grade silicone scar therapies. Silagen 100% Pure Silicone Gel is available in 15- or 30-g airless pumps. The Silagen line also includes a wide variety of silicone gel sheets, strips, and shapes with advanced adhesion technology and optimal silicone thickness. The gel has a silky feel and fast drying time. Silagen is physician dispensed. For more information, visit www.silagen.com.

If you would like your product included in Product News, please e-mail a press release to the Editorial Office at cutis@frontlinemedcom.com.

Epiduo Forte Gel

Galderma Laboratories, LP, announces US Food and Drug Administration approval of antibiotic-free Epiduo Forte (adapalene 0.3% and benzoyl peroxide 2.5%) Gel for the once-daily topical treatment of acne vulgaris. Epiduo Forte Gel contains a high concentration of adapalene, which works to unclog blocked pores and inhibits the release of proinflammatory mediators. Benzoyl peroxide offers antimicrobial properties. Epiduo Forte Gel can be considered for long-term use in patients with moderate to severe acne. The formulation is offered in a pump to provide convenient once-daily dosing. Epiduo Forte Gel will be available by prescription in early September 2015. For more information, visit www.galdermausa.com.

Odomzo

Novartis Pharmaceuticals Corporation obtains US Food and Drug Administration approval of Odomzo (sonidegib) 200-mg capsules for the treatment of adult patients with locally advanced basal cell carcinoma that has recurred following surgery or radiation therapy, or those who are not candidates for surgery or radiation therapy. Odomzo is an oral selective smoothened (SMO) inhibitor. SMO is a molecule that regulates the hedgehog signaling pathway, which plays a critical role in stem cell maintenance and tissue repair as well as in advanced basal cell carcinoma. For more information, visit www.novartis.com.

Physical Matte UV Defense SPF 50

SkinCeuticals introduces Physical Matte UV Defense SPF 50 sunscreen. This 100% mineral sunscreen is formulated with oil-absorbing powders to help minimize the appearance of sweat and oil to ensure a long-lasting matte finish while also providing broad-spectrum UVA/UVB protection. Physical Matte UV DefenseSPF 50 sunscreen is formulated for those with normal, combination, or oily skin with an uneven texture that is prone to shine. The mousse texture enhances application. It can be used alone or under makeup. For more information, visit www.skinceuticals.com.

Silagen Scar Refinement System

NewMedical Technology, Inc, introduces the Silagen Scar Refinement System, a line of 100% medical-grade silicone scar therapies. Silagen 100% Pure Silicone Gel is available in 15- or 30-g airless pumps. The Silagen line also includes a wide variety of silicone gel sheets, strips, and shapes with advanced adhesion technology and optimal silicone thickness. The gel has a silky feel and fast drying time. Silagen is physician dispensed. For more information, visit www.silagen.com.

If you would like your product included in Product News, please e-mail a press release to the Editorial Office at cutis@frontlinemedcom.com.

Epiduo Forte Gel

Galderma Laboratories, LP, announces US Food and Drug Administration approval of antibiotic-free Epiduo Forte (adapalene 0.3% and benzoyl peroxide 2.5%) Gel for the once-daily topical treatment of acne vulgaris. Epiduo Forte Gel contains a high concentration of adapalene, which works to unclog blocked pores and inhibits the release of proinflammatory mediators. Benzoyl peroxide offers antimicrobial properties. Epiduo Forte Gel can be considered for long-term use in patients with moderate to severe acne. The formulation is offered in a pump to provide convenient once-daily dosing. Epiduo Forte Gel will be available by prescription in early September 2015. For more information, visit www.galdermausa.com.

Odomzo

Novartis Pharmaceuticals Corporation obtains US Food and Drug Administration approval of Odomzo (sonidegib) 200-mg capsules for the treatment of adult patients with locally advanced basal cell carcinoma that has recurred following surgery or radiation therapy, or those who are not candidates for surgery or radiation therapy. Odomzo is an oral selective smoothened (SMO) inhibitor. SMO is a molecule that regulates the hedgehog signaling pathway, which plays a critical role in stem cell maintenance and tissue repair as well as in advanced basal cell carcinoma. For more information, visit www.novartis.com.

Physical Matte UV Defense SPF 50

SkinCeuticals introduces Physical Matte UV Defense SPF 50 sunscreen. This 100% mineral sunscreen is formulated with oil-absorbing powders to help minimize the appearance of sweat and oil to ensure a long-lasting matte finish while also providing broad-spectrum UVA/UVB protection. Physical Matte UV DefenseSPF 50 sunscreen is formulated for those with normal, combination, or oily skin with an uneven texture that is prone to shine. The mousse texture enhances application. It can be used alone or under makeup. For more information, visit www.skinceuticals.com.

Silagen Scar Refinement System

NewMedical Technology, Inc, introduces the Silagen Scar Refinement System, a line of 100% medical-grade silicone scar therapies. Silagen 100% Pure Silicone Gel is available in 15- or 30-g airless pumps. The Silagen line also includes a wide variety of silicone gel sheets, strips, and shapes with advanced adhesion technology and optimal silicone thickness. The gel has a silky feel and fast drying time. Silagen is physician dispensed. For more information, visit www.silagen.com.

If you would like your product included in Product News, please e-mail a press release to the Editorial Office at cutis@frontlinemedcom.com.

Facial rejuvenation has become increasingly popular, with nonsurgical and noninvasive procedures comprising a large part of aesthetic practice. According to the American Society for Aesthetic Plastic Surgery, Americans spent $12 billion on cosmetic procedures in 2014, with more than 10 million surgical and nonsurgical procedures performed. The top 5 nonsurgical procedures for both men and women combined were botulinum toxin, hyaluronic acid (HA), hair removal, chemical peel, and microdermabrasion.¹

The first dermal filler used was bovine collagen, which was approved by the US Food and Drug Administration (FDA) in 1981. Despite its efficacy in the correction of facial rhytides, bovine collagen required allergy testing prior to use and was discontinued in 2010. Dermal fillers have evolved over the years, and newer products that are superior to earlier fillers with regard to longevity, safety, and tolerability and that do not require allergy testing have become available; however, advances in the use of dermal fillers are not only related to the development of newer products but also to evolving injection techniques. Initially, the aim of treatment with dermal fillers was to correct lines and wrinkles, but an increased understanding of the complex changes that occur with aging have changed our approach to one of volume replacement, with an emphasis on volume restoration in the midface. This approach requires an in-depth understanding of facial anatomy as well as the interactions of the skin, soft tissue, muscle, and bone. Furthermore, placement of filler in specific fat compartments can provide a more natural appearance and an all-around youthful face.² In this article, we discuss HA fillers that have gained FDA approval within the last 5 years (Table).

Overview of HA Fillers

Hyaluronic acid is a naturally occurring linear glycosaminoglycan with a disaccharide unit, which repeats several thousand times.³ Hyaluronic acid is an essential part of the extracellular matrix of many tissues including the dermis and plays an important role in tissue growth, development, and wound healing. Hyaluronic acid is hygroscopic and absorbs water extensively, thus creating volume.⁴ Treatment with HA fillers is popular, as they are biocompatible and have a low potential for allergic reactions. They also are easy to use and reversible.⁴ The first HA filler to gain FDA approval was Restylane (Galderma  Laboratories, LP). Currently, several HA fillers are approved in the United States, and each product differs from the others in polymer chain length, degree of HA concentration, particle size, gel consistency, gel hardness, gel viscosity, and degree of water solubility, as well as amount and degree of cross-linking. Cross-linking is essential to avoid enzymatic degradation by endogenous hyaluronidase when injected into the skin and thus to prolong the product’s half-life.⁵ Cross-linkers used to manufacture HA fillers include 1,4-butanediol diglycidyl ether and divinyl sulfone. More concentrated products with a greater degree of cross-linking provide increased longevity, but they are associated with a higher risk for inflammation and nodule formation. The elastic modulus (G′) is a measure of the firmness of dermal fillers, describing their resistance to deformation. Materials with a higher G′ are stiffer and are meant for deeper injections. Hyaluronic acid fillers can be further classified as biphasic or monophasic. Biphasic fillers (eg, Restylane, Perlane [Galderma Laboratories, LP]) contain a range of microsphere sizes, while monophasic fillers (eg, Juvéderm [Allergan, Inc], Belotero Balance [Merz North America, Inc]) contain homogeneous microspheres. Although randomized clinical trials have reported comparable efficacy and durability of biphasic and monophasic fillers when used to treat the nasolabial folds,^6-8 monophasic HA fillers are more cohesive and may not migrate as much following injection.

Restylane Family

Restylane was the first FDA-approved HA filler, gaining its approval in 2003. Restylane is a nonanimal stabilized HA (NASHA) that is produced from the fermentation of equine streptococci. It is cross-linked with 1,4-butanediol diglycidyl ether with a 1% degree of cross-linking. Restylane has an HA concentration of 20 mg/mL. The particle size range of Restylane and Restylane-L is 330 to 430 mm. Restylane (and also Perlane) get passed through sizing screens via sieves and are quantified by their size. The longevity of HA fillers is approximately 6 months; however, various factors affect the product’s longevity, such as the degree of cross-linking, treatment area, and the patient’s metabolism. Restylane-L, which was FDA approved in 2012, is a newer product with 0.3% lidocaine incorporated into the syringe itself. It was the first product from the Restylane range to be approved for lip augmentation. The addition of lidocaine (designated by the L in the product name) does not affect the longevity of a filler.⁹

The newest FDA-approved HA filler was Restylane Silk (approved in 2014), which has been specifically designed for lip augmentation and correction of perioral rhytides. To avoid postprocedural swelling, it generally is recommended that Restylane Silk be injected slowly. If required, a short course of oral prednisone may be administered after the procedure to treat any edema. Restylane Silk is less viscous than Restylane and requires less pressure to inject. Therefore, it is more suited for treatment of fine perioral lines, as it flows more easily. Because it contains 0.3% lidocaine, discomfort usually is minimal, with treatment lasting approximately 30 to 60 minutes. In the author’s experience (G.G.), Restylane Silk provides a softer correction, though one has to be careful to inject slowly to avoid postinjection swelling. Restylane Silk also may be suitable for neck rejuvenation (off label), but several treatment sessions usually are required. Patients should be warned that they are likely to experience ecchymoses. In our experience, the effects of Restylane Silk injections last approximately 6 to 9 months.

Juvéderm Family

The first Juvéderm product was approved by the FDA in 2006. Juvéderm is a bacterium-derived NASHA. Injectable gel formulations of Juvéderm, including Juvéderm Ultra and Juvéderm Ultra Plus, are FDA approved for the correction of moderate to severe facial wrinkles and folds. The first products in the Juvéderm line were produced using a technology called Hylacross technology, with cohesive molecules of cross-linked HA. In contrast to the sizing technology used by Restylane and Perlane, the Hylacross technology does not break up the cross-linked HA by passing the product through sizing screens via sieves, but instead produces monophasic gels. These Juvéderm products have a high concentration of cross-linked HAs, which accounts for their longevity, and they are soft and easy to use.

Juvéderm Voluma XC was FDA approved in 2013. It is a 20-mg/mL, smooth, highly cohesive, viscous HA, gel that is manufactured using Vycross technology, a combination of low- and high-molecular-weight HA, and it is the only HA filler that is indicated for deep injection for cheek augmentation,¹⁰ as it creates a lift due to its higher G′ and a low swelling capacity, with results lasting up to 2 years. The mean volume administered over the initial 4-week period of one study was 5.1 mL.¹¹

Belotero Balance

Belotero Balance was approved by the FDA in 2011 for the correction of moderate to severe facial wrinkles and folds (eg, nasolabial folds).¹² Belotero Balance is an HA filler with a cohesive polydensified matrix technology and low elasticity and viscosity. It has the lowest G′ of the currently available dermal fillers¹² and therefore is associated with increased injection precision. Belotero Balance is ideal for superficial injections,¹³ such as forehead lines, vermilion border, tear trough, atrophic scars, and neck lines (off label). Some clinicians reconstitute Belotero Balance with lidocaine (off label) to provide a more pain-free procedure. In our experience, results typically last at least 6 to 8 months.

Complications

Hyaluronic acid fillers share the same adverse events across the product lines. The most common reactions include erythema, swelling, and bruising, which often are unavoidable and may be considered expected effects. Less-frequent events include contour irregularities; product migration; bluish discoloration known as the Tyndall effect, which is more likely to occur with superficial injections; nodules; infection at the injection site; scarring; and vascular occlusion, potentially leading to blindness.¹⁴ These more severe complications often can be avoided. Appropriate skin preparation and a sterile technique are critical in preventing infections, while deep placement of filler material reduces the risk for Tyndall effect, nodules, and scarring. Skin necrosis occurs by external compression of the blood supply by the product or occlusion via direct injection into a vessel. Aspirating prior to injection, administering lower volumes, and tenting the skin to inject more superficially can reduce the risk for skin necrosis. Every clinician needs to be able to rapidly recognize the signs of necrosis and to administer urgent therapy, such as the application of warm gauze and nitroglycerin paste, tapping the area to facilitate vasodilatation, and injecting hyaluronidase when required.

On the Horizon

Other dermal fillers that may gain FDA approval in the next few years include Teosyal (Laboratories  Teoxane Geneva),⁶ a new range of monophasic NASHA products that provide high viscosity and elasticity with results lasting 6 to 9 months, and potentially Juvéderm Volbella, a smooth, nonparticle, viscous HA gel developed specifically for the lip area with results lasting up to 1 year.¹⁵

Conclusion

Over the last decade, the popularity of dermal fillers has steadily increased, and fillers have become a cornerstone of aesthetic medicine. The increased number of available products necessitates thorough knowledge by the treating physician to ensure optimal outcomes. There is no universal filler that can achieve ideal outcomes in all anatomic sites or in all patients. Often a combination approach may be ideal, such as the use of a product with a higher G′ for re-volumization, followed by a filler with a lower G′ for superficial injection. Some patients may also benefit from a combination of both dermal fillers and neurotoxin injections, either on the same day or at separate visits, which may increase the longevity of the filler.

Facial rejuvenation has become increasingly popular, with nonsurgical and noninvasive procedures comprising a large part of aesthetic practice. According to the American Society for Aesthetic Plastic Surgery, Americans spent $12 billion on cosmetic procedures in 2014, with more than 10 million surgical and nonsurgical procedures performed. The top 5 nonsurgical procedures for both men and women combined were botulinum toxin, hyaluronic acid (HA), hair removal, chemical peel, and microdermabrasion.¹

The first dermal filler used was bovine collagen, which was approved by the US Food and Drug Administration (FDA) in 1981. Despite its efficacy in the correction of facial rhytides, bovine collagen required allergy testing prior to use and was discontinued in 2010. Dermal fillers have evolved over the years, and newer products that are superior to earlier fillers with regard to longevity, safety, and tolerability and that do not require allergy testing have become available; however, advances in the use of dermal fillers are not only related to the development of newer products but also to evolving injection techniques. Initially, the aim of treatment with dermal fillers was to correct lines and wrinkles, but an increased understanding of the complex changes that occur with aging have changed our approach to one of volume replacement, with an emphasis on volume restoration in the midface. This approach requires an in-depth understanding of facial anatomy as well as the interactions of the skin, soft tissue, muscle, and bone. Furthermore, placement of filler in specific fat compartments can provide a more natural appearance and an all-around youthful face.² In this article, we discuss HA fillers that have gained FDA approval within the last 5 years (Table).

Overview of HA Fillers

Hyaluronic acid is a naturally occurring linear glycosaminoglycan with a disaccharide unit, which repeats several thousand times.³ Hyaluronic acid is an essential part of the extracellular matrix of many tissues including the dermis and plays an important role in tissue growth, development, and wound healing. Hyaluronic acid is hygroscopic and absorbs water extensively, thus creating volume.⁴ Treatment with HA fillers is popular, as they are biocompatible and have a low potential for allergic reactions. They also are easy to use and reversible.⁴ The first HA filler to gain FDA approval was Restylane (Galderma  Laboratories, LP). Currently, several HA fillers are approved in the United States, and each product differs from the others in polymer chain length, degree of HA concentration, particle size, gel consistency, gel hardness, gel viscosity, and degree of water solubility, as well as amount and degree of cross-linking. Cross-linking is essential to avoid enzymatic degradation by endogenous hyaluronidase when injected into the skin and thus to prolong the product’s half-life.⁵ Cross-linkers used to manufacture HA fillers include 1,4-butanediol diglycidyl ether and divinyl sulfone. More concentrated products with a greater degree of cross-linking provide increased longevity, but they are associated with a higher risk for inflammation and nodule formation. The elastic modulus (G′) is a measure of the firmness of dermal fillers, describing their resistance to deformation. Materials with a higher G′ are stiffer and are meant for deeper injections. Hyaluronic acid fillers can be further classified as biphasic or monophasic. Biphasic fillers (eg, Restylane, Perlane [Galderma Laboratories, LP]) contain a range of microsphere sizes, while monophasic fillers (eg, Juvéderm [Allergan, Inc], Belotero Balance [Merz North America, Inc]) contain homogeneous microspheres. Although randomized clinical trials have reported comparable efficacy and durability of biphasic and monophasic fillers when used to treat the nasolabial folds,^6-8 monophasic HA fillers are more cohesive and may not migrate as much following injection.

Restylane Family

Restylane was the first FDA-approved HA filler, gaining its approval in 2003. Restylane is a nonanimal stabilized HA (NASHA) that is produced from the fermentation of equine streptococci. It is cross-linked with 1,4-butanediol diglycidyl ether with a 1% degree of cross-linking. Restylane has an HA concentration of 20 mg/mL. The particle size range of Restylane and Restylane-L is 330 to 430 mm. Restylane (and also Perlane) get passed through sizing screens via sieves and are quantified by their size. The longevity of HA fillers is approximately 6 months; however, various factors affect the product’s longevity, such as the degree of cross-linking, treatment area, and the patient’s metabolism. Restylane-L, which was FDA approved in 2012, is a newer product with 0.3% lidocaine incorporated into the syringe itself. It was the first product from the Restylane range to be approved for lip augmentation. The addition of lidocaine (designated by the L in the product name) does not affect the longevity of a filler.⁹

The newest FDA-approved HA filler was Restylane Silk (approved in 2014), which has been specifically designed for lip augmentation and correction of perioral rhytides. To avoid postprocedural swelling, it generally is recommended that Restylane Silk be injected slowly. If required, a short course of oral prednisone may be administered after the procedure to treat any edema. Restylane Silk is less viscous than Restylane and requires less pressure to inject. Therefore, it is more suited for treatment of fine perioral lines, as it flows more easily. Because it contains 0.3% lidocaine, discomfort usually is minimal, with treatment lasting approximately 30 to 60 minutes. In the author’s experience (G.G.), Restylane Silk provides a softer correction, though one has to be careful to inject slowly to avoid postinjection swelling. Restylane Silk also may be suitable for neck rejuvenation (off label), but several treatment sessions usually are required. Patients should be warned that they are likely to experience ecchymoses. In our experience, the effects of Restylane Silk injections last approximately 6 to 9 months.

Juvéderm Family

The first Juvéderm product was approved by the FDA in 2006. Juvéderm is a bacterium-derived NASHA. Injectable gel formulations of Juvéderm, including Juvéderm Ultra and Juvéderm Ultra Plus, are FDA approved for the correction of moderate to severe facial wrinkles and folds. The first products in the Juvéderm line were produced using a technology called Hylacross technology, with cohesive molecules of cross-linked HA. In contrast to the sizing technology used by Restylane and Perlane, the Hylacross technology does not break up the cross-linked HA by passing the product through sizing screens via sieves, but instead produces monophasic gels. These Juvéderm products have a high concentration of cross-linked HAs, which accounts for their longevity, and they are soft and easy to use.

Juvéderm Voluma XC was FDA approved in 2013. It is a 20-mg/mL, smooth, highly cohesive, viscous HA, gel that is manufactured using Vycross technology, a combination of low- and high-molecular-weight HA, and it is the only HA filler that is indicated for deep injection for cheek augmentation,¹⁰ as it creates a lift due to its higher G′ and a low swelling capacity, with results lasting up to 2 years. The mean volume administered over the initial 4-week period of one study was 5.1 mL.¹¹

Belotero Balance

Belotero Balance was approved by the FDA in 2011 for the correction of moderate to severe facial wrinkles and folds (eg, nasolabial folds).¹² Belotero Balance is an HA filler with a cohesive polydensified matrix technology and low elasticity and viscosity. It has the lowest G′ of the currently available dermal fillers¹² and therefore is associated with increased injection precision. Belotero Balance is ideal for superficial injections,¹³ such as forehead lines, vermilion border, tear trough, atrophic scars, and neck lines (off label). Some clinicians reconstitute Belotero Balance with lidocaine (off label) to provide a more pain-free procedure. In our experience, results typically last at least 6 to 8 months.

Complications

Hyaluronic acid fillers share the same adverse events across the product lines. The most common reactions include erythema, swelling, and bruising, which often are unavoidable and may be considered expected effects. Less-frequent events include contour irregularities; product migration; bluish discoloration known as the Tyndall effect, which is more likely to occur with superficial injections; nodules; infection at the injection site; scarring; and vascular occlusion, potentially leading to blindness.¹⁴ These more severe complications often can be avoided. Appropriate skin preparation and a sterile technique are critical in preventing infections, while deep placement of filler material reduces the risk for Tyndall effect, nodules, and scarring. Skin necrosis occurs by external compression of the blood supply by the product or occlusion via direct injection into a vessel. Aspirating prior to injection, administering lower volumes, and tenting the skin to inject more superficially can reduce the risk for skin necrosis. Every clinician needs to be able to rapidly recognize the signs of necrosis and to administer urgent therapy, such as the application of warm gauze and nitroglycerin paste, tapping the area to facilitate vasodilatation, and injecting hyaluronidase when required.

On the Horizon

Other dermal fillers that may gain FDA approval in the next few years include Teosyal (Laboratories  Teoxane Geneva),⁶ a new range of monophasic NASHA products that provide high viscosity and elasticity with results lasting 6 to 9 months, and potentially Juvéderm Volbella, a smooth, nonparticle, viscous HA gel developed specifically for the lip area with results lasting up to 1 year.¹⁵

Conclusion

Over the last decade, the popularity of dermal fillers has steadily increased, and fillers have become a cornerstone of aesthetic medicine. The increased number of available products necessitates thorough knowledge by the treating physician to ensure optimal outcomes. There is no universal filler that can achieve ideal outcomes in all anatomic sites or in all patients. Often a combination approach may be ideal, such as the use of a product with a higher G′ for re-volumization, followed by a filler with a lower G′ for superficial injection. Some patients may also benefit from a combination of both dermal fillers and neurotoxin injections, either on the same day or at separate visits, which may increase the longevity of the filler.

Facial rejuvenation has become increasingly popular, with nonsurgical and noninvasive procedures comprising a large part of aesthetic practice. According to the American Society for Aesthetic Plastic Surgery, Americans spent $12 billion on cosmetic procedures in 2014, with more than 10 million surgical and nonsurgical procedures performed. The top 5 nonsurgical procedures for both men and women combined were botulinum toxin, hyaluronic acid (HA), hair removal, chemical peel, and microdermabrasion.¹

The first dermal filler used was bovine collagen, which was approved by the US Food and Drug Administration (FDA) in 1981. Despite its efficacy in the correction of facial rhytides, bovine collagen required allergy testing prior to use and was discontinued in 2010. Dermal fillers have evolved over the years, and newer products that are superior to earlier fillers with regard to longevity, safety, and tolerability and that do not require allergy testing have become available; however, advances in the use of dermal fillers are not only related to the development of newer products but also to evolving injection techniques. Initially, the aim of treatment with dermal fillers was to correct lines and wrinkles, but an increased understanding of the complex changes that occur with aging have changed our approach to one of volume replacement, with an emphasis on volume restoration in the midface. This approach requires an in-depth understanding of facial anatomy as well as the interactions of the skin, soft tissue, muscle, and bone. Furthermore, placement of filler in specific fat compartments can provide a more natural appearance and an all-around youthful face.² In this article, we discuss HA fillers that have gained FDA approval within the last 5 years (Table).

Overview of HA Fillers

Hyaluronic acid is a naturally occurring linear glycosaminoglycan with a disaccharide unit, which repeats several thousand times.³ Hyaluronic acid is an essential part of the extracellular matrix of many tissues including the dermis and plays an important role in tissue growth, development, and wound healing. Hyaluronic acid is hygroscopic and absorbs water extensively, thus creating volume.⁴ Treatment with HA fillers is popular, as they are biocompatible and have a low potential for allergic reactions. They also are easy to use and reversible.⁴ The first HA filler to gain FDA approval was Restylane (Galderma  Laboratories, LP). Currently, several HA fillers are approved in the United States, and each product differs from the others in polymer chain length, degree of HA concentration, particle size, gel consistency, gel hardness, gel viscosity, and degree of water solubility, as well as amount and degree of cross-linking. Cross-linking is essential to avoid enzymatic degradation by endogenous hyaluronidase when injected into the skin and thus to prolong the product’s half-life.⁵ Cross-linkers used to manufacture HA fillers include 1,4-butanediol diglycidyl ether and divinyl sulfone. More concentrated products with a greater degree of cross-linking provide increased longevity, but they are associated with a higher risk for inflammation and nodule formation. The elastic modulus (G′) is a measure of the firmness of dermal fillers, describing their resistance to deformation. Materials with a higher G′ are stiffer and are meant for deeper injections. Hyaluronic acid fillers can be further classified as biphasic or monophasic. Biphasic fillers (eg, Restylane, Perlane [Galderma Laboratories, LP]) contain a range of microsphere sizes, while monophasic fillers (eg, Juvéderm [Allergan, Inc], Belotero Balance [Merz North America, Inc]) contain homogeneous microspheres. Although randomized clinical trials have reported comparable efficacy and durability of biphasic and monophasic fillers when used to treat the nasolabial folds,^6-8 monophasic HA fillers are more cohesive and may not migrate as much following injection.

Restylane Family

Restylane was the first FDA-approved HA filler, gaining its approval in 2003. Restylane is a nonanimal stabilized HA (NASHA) that is produced from the fermentation of equine streptococci. It is cross-linked with 1,4-butanediol diglycidyl ether with a 1% degree of cross-linking. Restylane has an HA concentration of 20 mg/mL. The particle size range of Restylane and Restylane-L is 330 to 430 mm. Restylane (and also Perlane) get passed through sizing screens via sieves and are quantified by their size. The longevity of HA fillers is approximately 6 months; however, various factors affect the product’s longevity, such as the degree of cross-linking, treatment area, and the patient’s metabolism. Restylane-L, which was FDA approved in 2012, is a newer product with 0.3% lidocaine incorporated into the syringe itself. It was the first product from the Restylane range to be approved for lip augmentation. The addition of lidocaine (designated by the L in the product name) does not affect the longevity of a filler.⁹

The newest FDA-approved HA filler was Restylane Silk (approved in 2014), which has been specifically designed for lip augmentation and correction of perioral rhytides. To avoid postprocedural swelling, it generally is recommended that Restylane Silk be injected slowly. If required, a short course of oral prednisone may be administered after the procedure to treat any edema. Restylane Silk is less viscous than Restylane and requires less pressure to inject. Therefore, it is more suited for treatment of fine perioral lines, as it flows more easily. Because it contains 0.3% lidocaine, discomfort usually is minimal, with treatment lasting approximately 30 to 60 minutes. In the author’s experience (G.G.), Restylane Silk provides a softer correction, though one has to be careful to inject slowly to avoid postinjection swelling. Restylane Silk also may be suitable for neck rejuvenation (off label), but several treatment sessions usually are required. Patients should be warned that they are likely to experience ecchymoses. In our experience, the effects of Restylane Silk injections last approximately 6 to 9 months.

Juvéderm Family

The first Juvéderm product was approved by the FDA in 2006. Juvéderm is a bacterium-derived NASHA. Injectable gel formulations of Juvéderm, including Juvéderm Ultra and Juvéderm Ultra Plus, are FDA approved for the correction of moderate to severe facial wrinkles and folds. The first products in the Juvéderm line were produced using a technology called Hylacross technology, with cohesive molecules of cross-linked HA. In contrast to the sizing technology used by Restylane and Perlane, the Hylacross technology does not break up the cross-linked HA by passing the product through sizing screens via sieves, but instead produces monophasic gels. These Juvéderm products have a high concentration of cross-linked HAs, which accounts for their longevity, and they are soft and easy to use.

Juvéderm Voluma XC was FDA approved in 2013. It is a 20-mg/mL, smooth, highly cohesive, viscous HA, gel that is manufactured using Vycross technology, a combination of low- and high-molecular-weight HA, and it is the only HA filler that is indicated for deep injection for cheek augmentation,¹⁰ as it creates a lift due to its higher G′ and a low swelling capacity, with results lasting up to 2 years. The mean volume administered over the initial 4-week period of one study was 5.1 mL.¹¹

Belotero Balance

Belotero Balance was approved by the FDA in 2011 for the correction of moderate to severe facial wrinkles and folds (eg, nasolabial folds).¹² Belotero Balance is an HA filler with a cohesive polydensified matrix technology and low elasticity and viscosity. It has the lowest G′ of the currently available dermal fillers¹² and therefore is associated with increased injection precision. Belotero Balance is ideal for superficial injections,¹³ such as forehead lines, vermilion border, tear trough, atrophic scars, and neck lines (off label). Some clinicians reconstitute Belotero Balance with lidocaine (off label) to provide a more pain-free procedure. In our experience, results typically last at least 6 to 8 months.

Complications

Hyaluronic acid fillers share the same adverse events across the product lines. The most common reactions include erythema, swelling, and bruising, which often are unavoidable and may be considered expected effects. Less-frequent events include contour irregularities; product migration; bluish discoloration known as the Tyndall effect, which is more likely to occur with superficial injections; nodules; infection at the injection site; scarring; and vascular occlusion, potentially leading to blindness.¹⁴ These more severe complications often can be avoided. Appropriate skin preparation and a sterile technique are critical in preventing infections, while deep placement of filler material reduces the risk for Tyndall effect, nodules, and scarring. Skin necrosis occurs by external compression of the blood supply by the product or occlusion via direct injection into a vessel. Aspirating prior to injection, administering lower volumes, and tenting the skin to inject more superficially can reduce the risk for skin necrosis. Every clinician needs to be able to rapidly recognize the signs of necrosis and to administer urgent therapy, such as the application of warm gauze and nitroglycerin paste, tapping the area to facilitate vasodilatation, and injecting hyaluronidase when required.

On the Horizon

Other dermal fillers that may gain FDA approval in the next few years include Teosyal (Laboratories  Teoxane Geneva),⁶ a new range of monophasic NASHA products that provide high viscosity and elasticity with results lasting 6 to 9 months, and potentially Juvéderm Volbella, a smooth, nonparticle, viscous HA gel developed specifically for the lip area with results lasting up to 1 year.¹⁵

Conclusion

Over the last decade, the popularity of dermal fillers has steadily increased, and fillers have become a cornerstone of aesthetic medicine. The increased number of available products necessitates thorough knowledge by the treating physician to ensure optimal outcomes. There is no universal filler that can achieve ideal outcomes in all anatomic sites or in all patients. Often a combination approach may be ideal, such as the use of a product with a higher G′ for re-volumization, followed by a filler with a lower G′ for superficial injection. Some patients may also benefit from a combination of both dermal fillers and neurotoxin injections, either on the same day or at separate visits, which may increase the longevity of the filler.

Question: Which of the following statements regarding statutory caps on malpractice damages is best?

A. All states have such a statutory provision.

B. The provision limits the recovery of both economic and noneconomic losses.

C. It’s constitutional.

D. It’s not constitutional.

E. Whether it’s constitutional depends on the jurisdiction.

Answer: E. In 1975, California enacted its historic Medical Injury Compensation Reform Act (MICRA),¹ the state legislature declaring that there was “a major health care crisis in the State of California attributable to skyrocketing malpractice premium costs and resulting in a potential breakdown of the health delivery system.”

The rationale was to provide some predictability, because noneconomic damages are difficult to quantify, and jury sympathy may result in unrealistically high payments. It was believed that damages for pain and suffering, for example, often contributed to runaway jury verdicts, prompting one indignant observer to write: “In making arguments for pain and suffering awards, both sides attempt to win the jurors’ sympathies with highly emotional evidence. A blind plaintiff will receive careful instruction to come to court with his [guide] dog, and to dab at his eyes with a handkerchief.”²

One of the main provisions of MICRA is to limit noneconomic recovery for injuries arising out of medical negligence. It caps noneconomic damages – for example, pain and suffering, disfigurement, emotional distress, loss of consortium, and other nonpecuniary losses – at $250,000. The law does not restrict recovery of economic damages such as wage loss, medical expenses, and future lost income.

California is the pioneer state to institute this tort reform measure, and about a dozen other states have followed suit, such as Proposition 12 in Texas, which limits noneconomic damages to $750,000 – $250,000 from the defendant doctor and $500,000 from the hospital.

Many tort reformists hail MICRA as the prototype success story, crediting it for bringing California’s malpractice insurance premiums from one of the highest levels in the nation to one of its lowest. A 2004 study reported that states with caps have a loss ratio (losses plus costs over premiums) that is 12% lower than in those without damage caps.³ Lower premiums in turn are linked to greater physician entry into the locality, especially for high-risk specialists.

In addition, caps may have a salutary effect on the wasteful practice of defensive medicine. A 2007 report by the American Medical Association confirms and extends an earlier study that reached such conclusions.

However, recent medical malpractice rates are generally no longer rising or even falling – both in states that had enacted tort reform and in states that had not. This may mean that other interventions such as medical error recognition and reduction are also effective.

Unsurprisingly, caps on damages have been challenged on constitutional grounds, as a violation of the equal rights amendment and the patient’s right to a jury trial. Two recent cases with divergent results – one on California, and the other in Florida – illustrate the state of flux over this controversy.

In Chan v. Curran, the plaintiff sought to relitigate the constitutionality of the California damage cap, but the appellate court ruled for the doctor defendant.⁴ The case alleged a wrongful death when the patient died from hemorrhage related to warfarin (Coumadin) use during open heart surgery.

The plaintiff argued that MICRA’s rationale was irrelevant, because there was no longer a malpractice insurance crisis in California – thus, restrictions placed on the quantum of damages are not rationally related to any legitimate state interest.

Furthermore, by limiting the amount of noneconomic damages to $250,000, MICRA violated equal protection and discouraged or inhibited attorneys from taking up malpractice cases on a contingency fee basis. Finally, the plaintiff argued that under the statute, a litigant is deprived of the right to a jury trial.

The court rejected all of these arguments, and reaffirmed the constitutionality of MICRA in line with earlier decisions that began with California’s Supreme Court decision in the Fein v. Permanente Medical Group case.⁵

On the other hand, the recent case of Estate of Michelle Evette McCall v. U.S. found the Florida Supreme Court ruling for the plaintiff.⁶ There, the court deemed unconstitutional Florida’s statute limiting wrongful death damages in medical malpractice to $1 million.

The case involved a young mother who died of massive hemorrhage following a cesarean section. In a 5-2 decision, the court held that the statute was arbitrary, reasoning that “the statutory cap on wrongful death noneconomic damages fails because it imposes unfair and illogical burdens on injured parties.”

Unlike California, the Florida court found that the cap bears no rational relationship to any perceived malpractice insurance crisis. And, while saving a modest amount for many, the statute imposed devastating costs on those who are most grievously injured, as well as on cases affecting multiple claimants.

The court commented that “the finding by the Legislature and the Task Force that Florida was in the midst of a bona fide medical malpractice crisis, threatening the access of Floridians to health care, is dubious and questionable at the very best.” The court also noted that four malpractice carriers actually increased their net income by more than 4,300% between 2003 and 2010.

In 2010, the Illinois Supreme Court also held in Lebron v. Gottlieb Memorial Hospital that the state’s $500,000 cap for noneconomic damages was unconstitutional, being in violation of the separation of powers doctrine.⁷ Only judges are empowered to reduce excessive verdicts, termed a remittitur. Thus, a statutory damage cap amounted to a “legislative remittitur” that invaded the power of the judiciary and violated the constitutional requirement of separation of powers.

The battle over caps continues unabated, with the trend appearing to favor the plaintiff bar. Florida’s ruling was the eighth state supreme court decision that held damage caps unconstitutional, joining Alabama, Georgia, Illinois, Missouri, New Hampshire, Oregon, and Washington. Five other states – Arizona, Arkansas, Kentucky, Pennsylvania, and Wyoming – already have state constitutional prohibitions on damage caps.

References

1. Medical Injury Compensation Reform Act of 1975, Cal. Civ. Proc. Code § 3333.2 (West 1982).

2. O’Connell, J. Offers That Can’t Be Refused: Foreclosure of Personal Injury Claims by Defendants’ Prompt Tender of Claimants’ Net Economic Losses. 77 N.W.U.L. Rev. 589, 591 (1982).

3. Thorpe, K. The Medical Malpractice Crisis: Recent Trends and the Impact of State Tort Reforms, Health Affairs 2004, Jan 21 [doi:10.1377/hlthaff.w4.20].

4. Chan v. Curran, 237 Cal. App. 4th 601 (Cal.Ct.App. 2015).

5. Fein v. Permanente Medical Group, 695 P.2d 665 (Cal. 1985).

6. Estate of Michelle Evette McCall v. U.S., 2014 Fla. LEXIS 933 (Fla. Mar. 13, 2014).

7. Lebron v. Gottlieb Memorial Hospital, 930 N.E.2d 895 (Ill. 2010).

Dr. Tan is emeritus professor of medicine and former adjunct professor of law at the University of Hawaii, and currently directs the St. Francis International Center for Healthcare Ethics in Honolulu. This article is meant to be educational and does not constitute medical, ethical, or legal advice. Some of the articles in this series are adapted from the author’s 2006 book, “Medical Malpractice: Understanding the Law, Managing the Risk,” and his 2012 Halsbury treatise, “Medical Negligence and Professional Misconduct.” For additional information, readers may contact the author at siang@hawaii.edu.

Question: Which of the following statements regarding statutory caps on malpractice damages is best?

A. All states have such a statutory provision.

B. The provision limits the recovery of both economic and noneconomic losses.

C. It’s constitutional.

D. It’s not constitutional.

E. Whether it’s constitutional depends on the jurisdiction.

Answer: E. In 1975, California enacted its historic Medical Injury Compensation Reform Act (MICRA),¹ the state legislature declaring that there was “a major health care crisis in the State of California attributable to skyrocketing malpractice premium costs and resulting in a potential breakdown of the health delivery system.”

The rationale was to provide some predictability, because noneconomic damages are difficult to quantify, and jury sympathy may result in unrealistically high payments. It was believed that damages for pain and suffering, for example, often contributed to runaway jury verdicts, prompting one indignant observer to write: “In making arguments for pain and suffering awards, both sides attempt to win the jurors’ sympathies with highly emotional evidence. A blind plaintiff will receive careful instruction to come to court with his [guide] dog, and to dab at his eyes with a handkerchief.”²

One of the main provisions of MICRA is to limit noneconomic recovery for injuries arising out of medical negligence. It caps noneconomic damages – for example, pain and suffering, disfigurement, emotional distress, loss of consortium, and other nonpecuniary losses – at $250,000. The law does not restrict recovery of economic damages such as wage loss, medical expenses, and future lost income.

California is the pioneer state to institute this tort reform measure, and about a dozen other states have followed suit, such as Proposition 12 in Texas, which limits noneconomic damages to $750,000 – $250,000 from the defendant doctor and $500,000 from the hospital.

Many tort reformists hail MICRA as the prototype success story, crediting it for bringing California’s malpractice insurance premiums from one of the highest levels in the nation to one of its lowest. A 2004 study reported that states with caps have a loss ratio (losses plus costs over premiums) that is 12% lower than in those without damage caps.³ Lower premiums in turn are linked to greater physician entry into the locality, especially for high-risk specialists.

In addition, caps may have a salutary effect on the wasteful practice of defensive medicine. A 2007 report by the American Medical Association confirms and extends an earlier study that reached such conclusions.

However, recent medical malpractice rates are generally no longer rising or even falling – both in states that had enacted tort reform and in states that had not. This may mean that other interventions such as medical error recognition and reduction are also effective.

Unsurprisingly, caps on damages have been challenged on constitutional grounds, as a violation of the equal rights amendment and the patient’s right to a jury trial. Two recent cases with divergent results – one on California, and the other in Florida – illustrate the state of flux over this controversy.

In Chan v. Curran, the plaintiff sought to relitigate the constitutionality of the California damage cap, but the appellate court ruled for the doctor defendant.⁴ The case alleged a wrongful death when the patient died from hemorrhage related to warfarin (Coumadin) use during open heart surgery.

The plaintiff argued that MICRA’s rationale was irrelevant, because there was no longer a malpractice insurance crisis in California – thus, restrictions placed on the quantum of damages are not rationally related to any legitimate state interest.

Furthermore, by limiting the amount of noneconomic damages to $250,000, MICRA violated equal protection and discouraged or inhibited attorneys from taking up malpractice cases on a contingency fee basis. Finally, the plaintiff argued that under the statute, a litigant is deprived of the right to a jury trial.

The court rejected all of these arguments, and reaffirmed the constitutionality of MICRA in line with earlier decisions that began with California’s Supreme Court decision in the Fein v. Permanente Medical Group case.⁵

On the other hand, the recent case of Estate of Michelle Evette McCall v. U.S. found the Florida Supreme Court ruling for the plaintiff.⁶ There, the court deemed unconstitutional Florida’s statute limiting wrongful death damages in medical malpractice to $1 million.

The case involved a young mother who died of massive hemorrhage following a cesarean section. In a 5-2 decision, the court held that the statute was arbitrary, reasoning that “the statutory cap on wrongful death noneconomic damages fails because it imposes unfair and illogical burdens on injured parties.”

Unlike California, the Florida court found that the cap bears no rational relationship to any perceived malpractice insurance crisis. And, while saving a modest amount for many, the statute imposed devastating costs on those who are most grievously injured, as well as on cases affecting multiple claimants.

The court commented that “the finding by the Legislature and the Task Force that Florida was in the midst of a bona fide medical malpractice crisis, threatening the access of Floridians to health care, is dubious and questionable at the very best.” The court also noted that four malpractice carriers actually increased their net income by more than 4,300% between 2003 and 2010.

In 2010, the Illinois Supreme Court also held in Lebron v. Gottlieb Memorial Hospital that the state’s $500,000 cap for noneconomic damages was unconstitutional, being in violation of the separation of powers doctrine.⁷ Only judges are empowered to reduce excessive verdicts, termed a remittitur. Thus, a statutory damage cap amounted to a “legislative remittitur” that invaded the power of the judiciary and violated the constitutional requirement of separation of powers.

The battle over caps continues unabated, with the trend appearing to favor the plaintiff bar. Florida’s ruling was the eighth state supreme court decision that held damage caps unconstitutional, joining Alabama, Georgia, Illinois, Missouri, New Hampshire, Oregon, and Washington. Five other states – Arizona, Arkansas, Kentucky, Pennsylvania, and Wyoming – already have state constitutional prohibitions on damage caps.

References

1. Medical Injury Compensation Reform Act of 1975, Cal. Civ. Proc. Code § 3333.2 (West 1982).

2. O’Connell, J. Offers That Can’t Be Refused: Foreclosure of Personal Injury Claims by Defendants’ Prompt Tender of Claimants’ Net Economic Losses. 77 N.W.U.L. Rev. 589, 591 (1982).

3. Thorpe, K. The Medical Malpractice Crisis: Recent Trends and the Impact of State Tort Reforms, Health Affairs 2004, Jan 21 [doi:10.1377/hlthaff.w4.20].

4. Chan v. Curran, 237 Cal. App. 4th 601 (Cal.Ct.App. 2015).

5. Fein v. Permanente Medical Group, 695 P.2d 665 (Cal. 1985).

6. Estate of Michelle Evette McCall v. U.S., 2014 Fla. LEXIS 933 (Fla. Mar. 13, 2014).

7. Lebron v. Gottlieb Memorial Hospital, 930 N.E.2d 895 (Ill. 2010).

Dr. Tan is emeritus professor of medicine and former adjunct professor of law at the University of Hawaii, and currently directs the St. Francis International Center for Healthcare Ethics in Honolulu. This article is meant to be educational and does not constitute medical, ethical, or legal advice. Some of the articles in this series are adapted from the author’s 2006 book, “Medical Malpractice: Understanding the Law, Managing the Risk,” and his 2012 Halsbury treatise, “Medical Negligence and Professional Misconduct.” For additional information, readers may contact the author at siang@hawaii.edu.

Question: Which of the following statements regarding statutory caps on malpractice damages is best?

A. All states have such a statutory provision.

B. The provision limits the recovery of both economic and noneconomic losses.

C. It’s constitutional.

D. It’s not constitutional.

E. Whether it’s constitutional depends on the jurisdiction.

Answer: E. In 1975, California enacted its historic Medical Injury Compensation Reform Act (MICRA),¹ the state legislature declaring that there was “a major health care crisis in the State of California attributable to skyrocketing malpractice premium costs and resulting in a potential breakdown of the health delivery system.”

The rationale was to provide some predictability, because noneconomic damages are difficult to quantify, and jury sympathy may result in unrealistically high payments. It was believed that damages for pain and suffering, for example, often contributed to runaway jury verdicts, prompting one indignant observer to write: “In making arguments for pain and suffering awards, both sides attempt to win the jurors’ sympathies with highly emotional evidence. A blind plaintiff will receive careful instruction to come to court with his [guide] dog, and to dab at his eyes with a handkerchief.”²

One of the main provisions of MICRA is to limit noneconomic recovery for injuries arising out of medical negligence. It caps noneconomic damages – for example, pain and suffering, disfigurement, emotional distress, loss of consortium, and other nonpecuniary losses – at $250,000. The law does not restrict recovery of economic damages such as wage loss, medical expenses, and future lost income.

California is the pioneer state to institute this tort reform measure, and about a dozen other states have followed suit, such as Proposition 12 in Texas, which limits noneconomic damages to $750,000 – $250,000 from the defendant doctor and $500,000 from the hospital.

Many tort reformists hail MICRA as the prototype success story, crediting it for bringing California’s malpractice insurance premiums from one of the highest levels in the nation to one of its lowest. A 2004 study reported that states with caps have a loss ratio (losses plus costs over premiums) that is 12% lower than in those without damage caps.³ Lower premiums in turn are linked to greater physician entry into the locality, especially for high-risk specialists.

In addition, caps may have a salutary effect on the wasteful practice of defensive medicine. A 2007 report by the American Medical Association confirms and extends an earlier study that reached such conclusions.

However, recent medical malpractice rates are generally no longer rising or even falling – both in states that had enacted tort reform and in states that had not. This may mean that other interventions such as medical error recognition and reduction are also effective.

Unsurprisingly, caps on damages have been challenged on constitutional grounds, as a violation of the equal rights amendment and the patient’s right to a jury trial. Two recent cases with divergent results – one on California, and the other in Florida – illustrate the state of flux over this controversy.

In Chan v. Curran, the plaintiff sought to relitigate the constitutionality of the California damage cap, but the appellate court ruled for the doctor defendant.⁴ The case alleged a wrongful death when the patient died from hemorrhage related to warfarin (Coumadin) use during open heart surgery.

The plaintiff argued that MICRA’s rationale was irrelevant, because there was no longer a malpractice insurance crisis in California – thus, restrictions placed on the quantum of damages are not rationally related to any legitimate state interest.

Furthermore, by limiting the amount of noneconomic damages to $250,000, MICRA violated equal protection and discouraged or inhibited attorneys from taking up malpractice cases on a contingency fee basis. Finally, the plaintiff argued that under the statute, a litigant is deprived of the right to a jury trial.

The court rejected all of these arguments, and reaffirmed the constitutionality of MICRA in line with earlier decisions that began with California’s Supreme Court decision in the Fein v. Permanente Medical Group case.⁵

On the other hand, the recent case of Estate of Michelle Evette McCall v. U.S. found the Florida Supreme Court ruling for the plaintiff.⁶ There, the court deemed unconstitutional Florida’s statute limiting wrongful death damages in medical malpractice to $1 million.

The case involved a young mother who died of massive hemorrhage following a cesarean section. In a 5-2 decision, the court held that the statute was arbitrary, reasoning that “the statutory cap on wrongful death noneconomic damages fails because it imposes unfair and illogical burdens on injured parties.”

Unlike California, the Florida court found that the cap bears no rational relationship to any perceived malpractice insurance crisis. And, while saving a modest amount for many, the statute imposed devastating costs on those who are most grievously injured, as well as on cases affecting multiple claimants.

The court commented that “the finding by the Legislature and the Task Force that Florida was in the midst of a bona fide medical malpractice crisis, threatening the access of Floridians to health care, is dubious and questionable at the very best.” The court also noted that four malpractice carriers actually increased their net income by more than 4,300% between 2003 and 2010.

In 2010, the Illinois Supreme Court also held in Lebron v. Gottlieb Memorial Hospital that the state’s $500,000 cap for noneconomic damages was unconstitutional, being in violation of the separation of powers doctrine.⁷ Only judges are empowered to reduce excessive verdicts, termed a remittitur. Thus, a statutory damage cap amounted to a “legislative remittitur” that invaded the power of the judiciary and violated the constitutional requirement of separation of powers.

The battle over caps continues unabated, with the trend appearing to favor the plaintiff bar. Florida’s ruling was the eighth state supreme court decision that held damage caps unconstitutional, joining Alabama, Georgia, Illinois, Missouri, New Hampshire, Oregon, and Washington. Five other states – Arizona, Arkansas, Kentucky, Pennsylvania, and Wyoming – already have state constitutional prohibitions on damage caps.

References

1. Medical Injury Compensation Reform Act of 1975, Cal. Civ. Proc. Code § 3333.2 (West 1982).

2. O’Connell, J. Offers That Can’t Be Refused: Foreclosure of Personal Injury Claims by Defendants’ Prompt Tender of Claimants’ Net Economic Losses. 77 N.W.U.L. Rev. 589, 591 (1982).

3. Thorpe, K. The Medical Malpractice Crisis: Recent Trends and the Impact of State Tort Reforms, Health Affairs 2004, Jan 21 [doi:10.1377/hlthaff.w4.20].

4. Chan v. Curran, 237 Cal. App. 4th 601 (Cal.Ct.App. 2015).

5. Fein v. Permanente Medical Group, 695 P.2d 665 (Cal. 1985).

6. Estate of Michelle Evette McCall v. U.S., 2014 Fla. LEXIS 933 (Fla. Mar. 13, 2014).

7. Lebron v. Gottlieb Memorial Hospital, 930 N.E.2d 895 (Ill. 2010).

Dr. Tan is emeritus professor of medicine and former adjunct professor of law at the University of Hawaii, and currently directs the St. Francis International Center for Healthcare Ethics in Honolulu. This article is meant to be educational and does not constitute medical, ethical, or legal advice. Some of the articles in this series are adapted from the author’s 2006 book, “Medical Malpractice: Understanding the Law, Managing the Risk,” and his 2012 Halsbury treatise, “Medical Negligence and Professional Misconduct.” For additional information, readers may contact the author at siang@hawaii.edu.

An 81-year-old woman presented for evaluation of a nodule on the right labia majora that had been present for 1 year. She had a history of intertriginous psoriasis, and several biopsies were performed at an outside facility over the last 5 years that revealed psoriasis but were otherwise noncontributory. Physical examination revealed erythema and scaling on the buttocks with maceration in the intertriginous area (top) and the perineum associated with a verrucous nodule (bottom).

The Diagnosis: Verrucous Carcinoma

Biopsies of early lesions often may be difficult to interpret without clinicopathological correlation. Our patient’s tumor was associated with intertriginous psoriasis, which was the only abnormality previously noted on superficial biopsies performed at an outside facility. The patient was scheduled for an excisional biopsy due to the large tumor size and clinical suspicion that the prior biopsies were inadequate and failed to demonstrate the primary underlying pathology. Excisional biopsy of the verrucous tumor revealed epithelium composed of keratinocytes with glassy cytoplasm. Papillomatosis was noted along with an endophytic component of well-differentiated epithelial cells extending into the dermis in a bulbous pattern consistent with the verrucous carcinoma variant of squamous cell carcinoma (SCC)(Figure). Verrucous carcinoma often requires correlation with both the clinical and histopathologic findings for definitive diagnosis, as keratinocytes often appear to be well differentiated.¹

Excisional biopsy of the verrucous nodule revealed marked acanthosis of the epidermis and bulbous projections of epithelium extending into the dermis. The endophytic “pushing border” supported a diagnosis of verrucous carcinoma (H&E, original magnification ×100).

Verrucous carcinoma may begin as an innocuous papule that slowly grows into a large fungating tumor. Verrucous carcinomas typically are slow growing, exophytic, and low grade. The etiology of verrucous carcinoma is not clear, and the role of human papillomavirus (HPV) infection is controversial.² Best classified as a well-differentiated SCC, verrucous carcinoma rarely metastasizes but may invade adjacent tissues.

Differential diagnoses include a giant inflamed seborrheic keratosis, condyloma acuminatum, rupioid psoriasis, and inflammatory linear verrucous epidermal nevus (ILVEN). Although large and inflamed seborrheic keratoses may have squamous eddies that mimic SCC, seborrheic keratoses do not invade the dermis and typically have a well-circumscribed stuck-on appearance. Abnormal mitotic figures are not identified. Condylomas are genital warts caused by HPV infection that often are clustered, well circumscribed, and exophytic. Large lesions can be difficult to distinguish from verrucous carcinomas, and biopsy generally reveals koilocytes identified by perinuclear clearing and raisinlike nuclei. Immunohistochemical staining and in situ hybridization studies can be of value in diagnosis and in identifying those lesions that are at high risk for malignant transformation. High-risk condylomas are associated with HPV-16, HPV-18, HPV-31, HPV-33, HPV-35, and HPV-39, as well as other types, whereas low-risk condylomas are associated with HPV-6, HPV-11, HPV-42, and others.² Differentiating squamous cell hyperplasia from squamous cell carcinoma in situ also can be aided by immunohistochemistry. Squamous cell hyperplasia is usually negative for INK4 p16^Ink4A and p53 and exhibits variable Ki-67 staining. Differentiated squamous cell carcinoma in situ exhibits a profile that is p16^Ink4A negative, Ki-67 positive, and exhibits variable p53 staining.³ Basaloid and warty intraepithelial neoplasia is consistently p16^Ink4A positive, Ki-67 positive, and variably positive for p53.³ Therefore, p16 staining of high-grade areas is a useful biomarker that can help establish diagnosis of associated squamous cell carcinoma.⁴ The role of papillomaviruses in the development of nonmelanoma skin cancer is an area of active study, and research suggests that papillomaviruses may have a much greater role than previously suspected.⁵

At times, psoriasis may be markedly hyperkeratotic, clinically mimicking a verrucous neoplasm. This hyperkeratotic type of psoriasis is known as rupioid psoriasis. However, these psoriatic lesions are exophytic, are associated with spongiform pustules, and lack the atypia and endophytic pattern typically seen with verrucous carcinoma. An ILVEN also lacks atypia and an endophytic pattern and usually presents in childhood as a persistent linear plaque, rather than the verrucous plaque noted in our patient. Squamous cell carcinoma has been reported to arise in the setting of verrucoid ILVEN but is exceptionally uncommon.⁶

Successful treatment of verrucous carcinoma is best achieved by complete excision. Oral retinoids and immunomodulators such as imiquimod also may be of value.⁷ Our patient’s tumor qualifies as T2N0M0 because it was greater than 2 cm in size.⁸ A Breslow thickness of 2 mm or greater and Clark level IV are high-risk features associated with a worse prognosis, but clinical evaluation of our patient’s lymph nodes was unremarkable and no distant metastases were identified. Our patient continues to do well with no evidence of recurrence.

An 81-year-old woman presented for evaluation of a nodule on the right labia majora that had been present for 1 year. She had a history of intertriginous psoriasis, and several biopsies were performed at an outside facility over the last 5 years that revealed psoriasis but were otherwise noncontributory. Physical examination revealed erythema and scaling on the buttocks with maceration in the intertriginous area (top) and the perineum associated with a verrucous nodule (bottom).

The Diagnosis: Verrucous Carcinoma

Biopsies of early lesions often may be difficult to interpret without clinicopathological correlation. Our patient’s tumor was associated with intertriginous psoriasis, which was the only abnormality previously noted on superficial biopsies performed at an outside facility. The patient was scheduled for an excisional biopsy due to the large tumor size and clinical suspicion that the prior biopsies were inadequate and failed to demonstrate the primary underlying pathology. Excisional biopsy of the verrucous tumor revealed epithelium composed of keratinocytes with glassy cytoplasm. Papillomatosis was noted along with an endophytic component of well-differentiated epithelial cells extending into the dermis in a bulbous pattern consistent with the verrucous carcinoma variant of squamous cell carcinoma (SCC)(Figure). Verrucous carcinoma often requires correlation with both the clinical and histopathologic findings for definitive diagnosis, as keratinocytes often appear to be well differentiated.¹

Excisional biopsy of the verrucous nodule revealed marked acanthosis of the epidermis and bulbous projections of epithelium extending into the dermis. The endophytic “pushing border” supported a diagnosis of verrucous carcinoma (H&E, original magnification ×100).

Verrucous carcinoma may begin as an innocuous papule that slowly grows into a large fungating tumor. Verrucous carcinomas typically are slow growing, exophytic, and low grade. The etiology of verrucous carcinoma is not clear, and the role of human papillomavirus (HPV) infection is controversial.² Best classified as a well-differentiated SCC, verrucous carcinoma rarely metastasizes but may invade adjacent tissues.

Differential diagnoses include a giant inflamed seborrheic keratosis, condyloma acuminatum, rupioid psoriasis, and inflammatory linear verrucous epidermal nevus (ILVEN). Although large and inflamed seborrheic keratoses may have squamous eddies that mimic SCC, seborrheic keratoses do not invade the dermis and typically have a well-circumscribed stuck-on appearance. Abnormal mitotic figures are not identified. Condylomas are genital warts caused by HPV infection that often are clustered, well circumscribed, and exophytic. Large lesions can be difficult to distinguish from verrucous carcinomas, and biopsy generally reveals koilocytes identified by perinuclear clearing and raisinlike nuclei. Immunohistochemical staining and in situ hybridization studies can be of value in diagnosis and in identifying those lesions that are at high risk for malignant transformation. High-risk condylomas are associated with HPV-16, HPV-18, HPV-31, HPV-33, HPV-35, and HPV-39, as well as other types, whereas low-risk condylomas are associated with HPV-6, HPV-11, HPV-42, and others.² Differentiating squamous cell hyperplasia from squamous cell carcinoma in situ also can be aided by immunohistochemistry. Squamous cell hyperplasia is usually negative for INK4 p16^Ink4A and p53 and exhibits variable Ki-67 staining. Differentiated squamous cell carcinoma in situ exhibits a profile that is p16^Ink4A negative, Ki-67 positive, and exhibits variable p53 staining.³ Basaloid and warty intraepithelial neoplasia is consistently p16^Ink4A positive, Ki-67 positive, and variably positive for p53.³ Therefore, p16 staining of high-grade areas is a useful biomarker that can help establish diagnosis of associated squamous cell carcinoma.⁴ The role of papillomaviruses in the development of nonmelanoma skin cancer is an area of active study, and research suggests that papillomaviruses may have a much greater role than previously suspected.⁵

At times, psoriasis may be markedly hyperkeratotic, clinically mimicking a verrucous neoplasm. This hyperkeratotic type of psoriasis is known as rupioid psoriasis. However, these psoriatic lesions are exophytic, are associated with spongiform pustules, and lack the atypia and endophytic pattern typically seen with verrucous carcinoma. An ILVEN also lacks atypia and an endophytic pattern and usually presents in childhood as a persistent linear plaque, rather than the verrucous plaque noted in our patient. Squamous cell carcinoma has been reported to arise in the setting of verrucoid ILVEN but is exceptionally uncommon.⁶

Successful treatment of verrucous carcinoma is best achieved by complete excision. Oral retinoids and immunomodulators such as imiquimod also may be of value.⁷ Our patient’s tumor qualifies as T2N0M0 because it was greater than 2 cm in size.⁸ A Breslow thickness of 2 mm or greater and Clark level IV are high-risk features associated with a worse prognosis, but clinical evaluation of our patient’s lymph nodes was unremarkable and no distant metastases were identified. Our patient continues to do well with no evidence of recurrence.

An 81-year-old woman presented for evaluation of a nodule on the right labia majora that had been present for 1 year. She had a history of intertriginous psoriasis, and several biopsies were performed at an outside facility over the last 5 years that revealed psoriasis but were otherwise noncontributory. Physical examination revealed erythema and scaling on the buttocks with maceration in the intertriginous area (top) and the perineum associated with a verrucous nodule (bottom).

The Diagnosis: Verrucous Carcinoma

Biopsies of early lesions often may be difficult to interpret without clinicopathological correlation. Our patient’s tumor was associated with intertriginous psoriasis, which was the only abnormality previously noted on superficial biopsies performed at an outside facility. The patient was scheduled for an excisional biopsy due to the large tumor size and clinical suspicion that the prior biopsies were inadequate and failed to demonstrate the primary underlying pathology. Excisional biopsy of the verrucous tumor revealed epithelium composed of keratinocytes with glassy cytoplasm. Papillomatosis was noted along with an endophytic component of well-differentiated epithelial cells extending into the dermis in a bulbous pattern consistent with the verrucous carcinoma variant of squamous cell carcinoma (SCC)(Figure). Verrucous carcinoma often requires correlation with both the clinical and histopathologic findings for definitive diagnosis, as keratinocytes often appear to be well differentiated.¹

Excisional biopsy of the verrucous nodule revealed marked acanthosis of the epidermis and bulbous projections of epithelium extending into the dermis. The endophytic “pushing border” supported a diagnosis of verrucous carcinoma (H&E, original magnification ×100).

Verrucous carcinoma may begin as an innocuous papule that slowly grows into a large fungating tumor. Verrucous carcinomas typically are slow growing, exophytic, and low grade. The etiology of verrucous carcinoma is not clear, and the role of human papillomavirus (HPV) infection is controversial.² Best classified as a well-differentiated SCC, verrucous carcinoma rarely metastasizes but may invade adjacent tissues.

Differential diagnoses include a giant inflamed seborrheic keratosis, condyloma acuminatum, rupioid psoriasis, and inflammatory linear verrucous epidermal nevus (ILVEN). Although large and inflamed seborrheic keratoses may have squamous eddies that mimic SCC, seborrheic keratoses do not invade the dermis and typically have a well-circumscribed stuck-on appearance. Abnormal mitotic figures are not identified. Condylomas are genital warts caused by HPV infection that often are clustered, well circumscribed, and exophytic. Large lesions can be difficult to distinguish from verrucous carcinomas, and biopsy generally reveals koilocytes identified by perinuclear clearing and raisinlike nuclei. Immunohistochemical staining and in situ hybridization studies can be of value in diagnosis and in identifying those lesions that are at high risk for malignant transformation. High-risk condylomas are associated with HPV-16, HPV-18, HPV-31, HPV-33, HPV-35, and HPV-39, as well as other types, whereas low-risk condylomas are associated with HPV-6, HPV-11, HPV-42, and others.² Differentiating squamous cell hyperplasia from squamous cell carcinoma in situ also can be aided by immunohistochemistry. Squamous cell hyperplasia is usually negative for INK4 p16^Ink4A and p53 and exhibits variable Ki-67 staining. Differentiated squamous cell carcinoma in situ exhibits a profile that is p16^Ink4A negative, Ki-67 positive, and exhibits variable p53 staining.³ Basaloid and warty intraepithelial neoplasia is consistently p16^Ink4A positive, Ki-67 positive, and variably positive for p53.³ Therefore, p16 staining of high-grade areas is a useful biomarker that can help establish diagnosis of associated squamous cell carcinoma.⁴ The role of papillomaviruses in the development of nonmelanoma skin cancer is an area of active study, and research suggests that papillomaviruses may have a much greater role than previously suspected.⁵

At times, psoriasis may be markedly hyperkeratotic, clinically mimicking a verrucous neoplasm. This hyperkeratotic type of psoriasis is known as rupioid psoriasis. However, these psoriatic lesions are exophytic, are associated with spongiform pustules, and lack the atypia and endophytic pattern typically seen with verrucous carcinoma. An ILVEN also lacks atypia and an endophytic pattern and usually presents in childhood as a persistent linear plaque, rather than the verrucous plaque noted in our patient. Squamous cell carcinoma has been reported to arise in the setting of verrucoid ILVEN but is exceptionally uncommon.⁶

Successful treatment of verrucous carcinoma is best achieved by complete excision. Oral retinoids and immunomodulators such as imiquimod also may be of value.⁷ Our patient’s tumor qualifies as T2N0M0 because it was greater than 2 cm in size.⁸ A Breslow thickness of 2 mm or greater and Clark level IV are high-risk features associated with a worse prognosis, but clinical evaluation of our patient’s lymph nodes was unremarkable and no distant metastases were identified. Our patient continues to do well with no evidence of recurrence.

Influenza vaccination is recommended for all patients aged 6 months and older, as long as they don’t have a contraindication, according to a report Aug. 7 in Morbidity and Mortality Weekly Report.

Trivalent influenza vaccines for the 2015-2016 season will contain hemagglutinin (HA) derived from an H1N1-like virus, an H3N2-like virus, and a B/Phuket/3073/2013-like (Yamagata lineage) virus. Quadrivalent vaccines will contain those components, as well as a B/Brisbane/60/2008-like (Victoria lineage) virus, the same virus recommended for quadrivalent formulations in the 2013-14 and 2014-15 seasons, ACIP said in a statement.

New FDA-approved vaccines include Afluria, the Fluzone Intradermal Quadrivalent vaccine (both approved in 2014 for adults aged 18-64 years), and an expanded age indication for Flublok, which is now indicated for adults aged 18 years and older.

The live attenuated influenza vaccine (LAIV) should not be used in certain populations, including those aged less than 2 years or greater than 49 years; children aged 2-17 years taking aspirin; pateints with severe allergic reactions to the vaccine; pregnant women; and those with egg allergies, among others. Either the LAIV or the inactivated influenza vaccine (IIV) is appropriate for administration in healthy children aged 2-8 years, ACIP said.

For a detailed explanation of the recommendations, see MMWR.

mrajaraman@frontlinemedcom.com

Influenza vaccination is recommended for all patients aged 6 months and older, as long as they don’t have a contraindication, according to a report Aug. 7 in Morbidity and Mortality Weekly Report.

Trivalent influenza vaccines for the 2015-2016 season will contain hemagglutinin (HA) derived from an H1N1-like virus, an H3N2-like virus, and a B/Phuket/3073/2013-like (Yamagata lineage) virus. Quadrivalent vaccines will contain those components, as well as a B/Brisbane/60/2008-like (Victoria lineage) virus, the same virus recommended for quadrivalent formulations in the 2013-14 and 2014-15 seasons, ACIP said in a statement.

New FDA-approved vaccines include Afluria, the Fluzone Intradermal Quadrivalent vaccine (both approved in 2014 for adults aged 18-64 years), and an expanded age indication for Flublok, which is now indicated for adults aged 18 years and older.

The live attenuated influenza vaccine (LAIV) should not be used in certain populations, including those aged less than 2 years or greater than 49 years; children aged 2-17 years taking aspirin; pateints with severe allergic reactions to the vaccine; pregnant women; and those with egg allergies, among others. Either the LAIV or the inactivated influenza vaccine (IIV) is appropriate for administration in healthy children aged 2-8 years, ACIP said.

For a detailed explanation of the recommendations, see MMWR.

mrajaraman@frontlinemedcom.com

Influenza vaccination is recommended for all patients aged 6 months and older, as long as they don’t have a contraindication, according to a report Aug. 7 in Morbidity and Mortality Weekly Report.

Trivalent influenza vaccines for the 2015-2016 season will contain hemagglutinin (HA) derived from an H1N1-like virus, an H3N2-like virus, and a B/Phuket/3073/2013-like (Yamagata lineage) virus. Quadrivalent vaccines will contain those components, as well as a B/Brisbane/60/2008-like (Victoria lineage) virus, the same virus recommended for quadrivalent formulations in the 2013-14 and 2014-15 seasons, ACIP said in a statement.

New FDA-approved vaccines include Afluria, the Fluzone Intradermal Quadrivalent vaccine (both approved in 2014 for adults aged 18-64 years), and an expanded age indication for Flublok, which is now indicated for adults aged 18 years and older.

The live attenuated influenza vaccine (LAIV) should not be used in certain populations, including those aged less than 2 years or greater than 49 years; children aged 2-17 years taking aspirin; pateints with severe allergic reactions to the vaccine; pregnant women; and those with egg allergies, among others. Either the LAIV or the inactivated influenza vaccine (IIV) is appropriate for administration in healthy children aged 2-8 years, ACIP said.

For a detailed explanation of the recommendations, see MMWR.

mrajaraman@frontlinemedcom.com

CHICAGO – Several modifiable risk factors predicted the development of anastomotic leak following elective colon resection, a large national analysis found.

“Preoperative smoking cessation, preoperative administration of oral antibiotic bowel preparation, and laparoscopic approach are modifiable factors that could reduce the risk of anastomotic leak,” Dr. Cindy Wu said at the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) National Conference.

Patrice Wendling/Frontline Medical News

Anastomotic leakage results in increased morbidity and mortality, yet the current literature analyzing risk factors for this complication is generally limited to retrospective studies of single institutions, she said.

To examine data from a larger sample of colectomy patients from multiple centers, the investigators used the NSQIP Participant Use Data File specifically targeted to colectomy to identify 14,848 patients who underwent elective colon resection from 2012 to 2013. Chi-square, Wald chi-square, and logistic regression analyses were performed examining patient factors (sex, race, comorbidities, smoking status, American Society of Anesthesiologists class, functional status, steroid use, and preoperative albumin), oncologic factors (chemotherapy, tumor stage, and presence or absence of disseminated cancer), and operative factors (wound class, mechanical bowel preparation, oral antibiotic preparation, surgical approach, colectomy site, surgical indication, and operative time).

In all, 3.4%, or 498 patients, experienced an anastomotic leak, which is consistent with the literature, Dr. Wu of Temple University in Philadelphia said. Of these patients, 101 required no intervention, while 272 required surgery and 125 needed percutaneous drainage. The mean age of the patients was 60.7 years and 57% were male.

In a univariate analysis, male sex (chi-square = 17.4; P less than .01), diabetes controlled with either oral medication or insulin (X^{2 =} 9.5; P less than .01), and smoking within the last year (X² = 20.4; P less than .01) were associated with a greater incidence of anastomotic leak.

Other risk factors that were significant in additional univariate analysis were ASA class (X² = 23.3; P = .0001), functional status (X² = 9.15; P = .01), 10% weight loss over the last 6 months (X² = 5.83; P = .02), wound class (X² = 10.8; P = .01), mechanical bowel preparation (X² = 5.89; P = .01), lack of oral antibiotic preparation (X² = 17.5; P less than .0001), open vs. laparoscopic/minimally invasive surgery (X² = 60.0; P less than .0001), chemotherapy in the last 90 days (X² = 23.1; P less than .0001), and presence of disseminated cancer (X² = 7.41; P = .01), Dr. Wu said.

With all of these factors taken into account in multivariate analysis, independent predictors of an increased risk of anastomotic leak were male sex (odds ratio, 1.74; P = .01), tobacco use (OR, 1.73; P = .03), and lack of a preoperative oral antibiotic bowel preparation (OR, 1.79; P less than .01).

Interestingly, use of a laparoscopic technique was protective against the development of anastomotic leakage (OR, 0.54; P less than .01), she said.

The authors reported having no relevant financial disclosures.

pwendling@frontlinemedcom.com

CHICAGO – Several modifiable risk factors predicted the development of anastomotic leak following elective colon resection, a large national analysis found.

“Preoperative smoking cessation, preoperative administration of oral antibiotic bowel preparation, and laparoscopic approach are modifiable factors that could reduce the risk of anastomotic leak,” Dr. Cindy Wu said at the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) National Conference.

Patrice Wendling/Frontline Medical News

Anastomotic leakage results in increased morbidity and mortality, yet the current literature analyzing risk factors for this complication is generally limited to retrospective studies of single institutions, she said.

To examine data from a larger sample of colectomy patients from multiple centers, the investigators used the NSQIP Participant Use Data File specifically targeted to colectomy to identify 14,848 patients who underwent elective colon resection from 2012 to 2013. Chi-square, Wald chi-square, and logistic regression analyses were performed examining patient factors (sex, race, comorbidities, smoking status, American Society of Anesthesiologists class, functional status, steroid use, and preoperative albumin), oncologic factors (chemotherapy, tumor stage, and presence or absence of disseminated cancer), and operative factors (wound class, mechanical bowel preparation, oral antibiotic preparation, surgical approach, colectomy site, surgical indication, and operative time).

In all, 3.4%, or 498 patients, experienced an anastomotic leak, which is consistent with the literature, Dr. Wu of Temple University in Philadelphia said. Of these patients, 101 required no intervention, while 272 required surgery and 125 needed percutaneous drainage. The mean age of the patients was 60.7 years and 57% were male.

In a univariate analysis, male sex (chi-square = 17.4; P less than .01), diabetes controlled with either oral medication or insulin (X^{2 =} 9.5; P less than .01), and smoking within the last year (X² = 20.4; P less than .01) were associated with a greater incidence of anastomotic leak.

Other risk factors that were significant in additional univariate analysis were ASA class (X² = 23.3; P = .0001), functional status (X² = 9.15; P = .01), 10% weight loss over the last 6 months (X² = 5.83; P = .02), wound class (X² = 10.8; P = .01), mechanical bowel preparation (X² = 5.89; P = .01), lack of oral antibiotic preparation (X² = 17.5; P less than .0001), open vs. laparoscopic/minimally invasive surgery (X² = 60.0; P less than .0001), chemotherapy in the last 90 days (X² = 23.1; P less than .0001), and presence of disseminated cancer (X² = 7.41; P = .01), Dr. Wu said.

With all of these factors taken into account in multivariate analysis, independent predictors of an increased risk of anastomotic leak were male sex (odds ratio, 1.74; P = .01), tobacco use (OR, 1.73; P = .03), and lack of a preoperative oral antibiotic bowel preparation (OR, 1.79; P less than .01).

Interestingly, use of a laparoscopic technique was protective against the development of anastomotic leakage (OR, 0.54; P less than .01), she said.

The authors reported having no relevant financial disclosures.

pwendling@frontlinemedcom.com

CHICAGO – Several modifiable risk factors predicted the development of anastomotic leak following elective colon resection, a large national analysis found.

“Preoperative smoking cessation, preoperative administration of oral antibiotic bowel preparation, and laparoscopic approach are modifiable factors that could reduce the risk of anastomotic leak,” Dr. Cindy Wu said at the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) National Conference.

Patrice Wendling/Frontline Medical News

Anastomotic leakage results in increased morbidity and mortality, yet the current literature analyzing risk factors for this complication is generally limited to retrospective studies of single institutions, she said.

To examine data from a larger sample of colectomy patients from multiple centers, the investigators used the NSQIP Participant Use Data File specifically targeted to colectomy to identify 14,848 patients who underwent elective colon resection from 2012 to 2013. Chi-square, Wald chi-square, and logistic regression analyses were performed examining patient factors (sex, race, comorbidities, smoking status, American Society of Anesthesiologists class, functional status, steroid use, and preoperative albumin), oncologic factors (chemotherapy, tumor stage, and presence or absence of disseminated cancer), and operative factors (wound class, mechanical bowel preparation, oral antibiotic preparation, surgical approach, colectomy site, surgical indication, and operative time).

In all, 3.4%, or 498 patients, experienced an anastomotic leak, which is consistent with the literature, Dr. Wu of Temple University in Philadelphia said. Of these patients, 101 required no intervention, while 272 required surgery and 125 needed percutaneous drainage. The mean age of the patients was 60.7 years and 57% were male.

In a univariate analysis, male sex (chi-square = 17.4; P less than .01), diabetes controlled with either oral medication or insulin (X^{2 =} 9.5; P less than .01), and smoking within the last year (X² = 20.4; P less than .01) were associated with a greater incidence of anastomotic leak.

Other risk factors that were significant in additional univariate analysis were ASA class (X² = 23.3; P = .0001), functional status (X² = 9.15; P = .01), 10% weight loss over the last 6 months (X² = 5.83; P = .02), wound class (X² = 10.8; P = .01), mechanical bowel preparation (X² = 5.89; P = .01), lack of oral antibiotic preparation (X² = 17.5; P less than .0001), open vs. laparoscopic/minimally invasive surgery (X² = 60.0; P less than .0001), chemotherapy in the last 90 days (X² = 23.1; P less than .0001), and presence of disseminated cancer (X² = 7.41; P = .01), Dr. Wu said.

With all of these factors taken into account in multivariate analysis, independent predictors of an increased risk of anastomotic leak were male sex (odds ratio, 1.74; P = .01), tobacco use (OR, 1.73; P = .03), and lack of a preoperative oral antibiotic bowel preparation (OR, 1.79; P less than .01).

Interestingly, use of a laparoscopic technique was protective against the development of anastomotic leakage (OR, 0.54; P less than .01), she said.

The authors reported having no relevant financial disclosures.

pwendling@frontlinemedcom.com

Trichilemmomas are benign follicular neoplasms that exhibit differentiation toward the outer root sheath of the pilosebaceous follicular epithelium.¹ Trichilemmomas clinically present as individual or multiple, slowly growing, verrucous papules appearing most commonly on the face or neck. The lesions may coalesce to form small plaques. Although trichilemmomas typically are isolated, patients with multiple trichilemmomas require a cancer screening workup due to their association with Cowden disease, which results from a mutation in the phosphatase and tensin homolog tumor suppressor gene, PTEN.² An easy way to remember the association between trichilemmomas and Cowden disease is to alter the spelling to “trichile-moo-moo,” using the “moo moo” sound of an animal cow as a clue linking the tumor to Cowden disease.

Histologically, trichilemmomas exhibit a lobular epidermal downgrowth into the dermis (Figure 1). The surface of the lesion may be hyperkeratotic and somewhat papillomatous. Cells toward the center of the lobule are pale staining, periodic acid–Schiff positive, and diastase labile due to high levels of intracellular glycogen (Figure 2). Cells toward the periphery of the lobule usually appear basophilic with a palisading arrangement of the peripheral cells. The entire lobule is enclosed within an eosinophilic basement membrane that stains positively with periodic acid–Schiff (Figure 2).¹ Consistent with the tumor’s differentiation toward the outer root sheath of the hair follicle, trichilemmomas have been reported to express CD34 focally or diffusely.³

Figure 1. A lobular trichilemmoma composed of aggregates of epithelial cells extending from the epidermis into the dermis. The cells of the tumor are composed of squamoid cells showing variable glycogen vacuolation (pale-staining cytoplasm) and there is a surrounding prominent basement membrane (arrow)(H&E, original magnification ×40).

Figure 2. High-power magnification showing the pale-staining cells comprising a trichilemmoma (asterisk) as well as peripheral palisading of the cells at the periphery of the lesion and a thickened surrounding membrane (arrow)(H&E, original magnification ×200).

Similar to trichilemmoma, inverted follicular keratosis (IFK) commonly presents as a solitary asymptomatic papule on the face. Inverted follicular keratosis is a somewhat controversial entity, with some authorities arguing IFK is a variant of verruca vulgaris or seborrheic keratosis. Histologically, IFKs can be differentiated by the presence of squamous eddies (concentric layers of squamous cells in a whorled pattern), which are diagnostic, and central longitudinal crypts that contain keratin and are lined by squamous epithelium.⁴ Basaloid cells can be seen at the periphery of the tumors; however, IFKs lack an eosinophilic basement membrane surrounding the tumor (Figure 3).

Figure 3. Sections of a biopsy from an inverted follicular keratosis show an endophytic lesion with acanthosis consisting of fairly uniform squamous cells with eosinophilic cytoplasm. Numerous squamous eddies can be seen (H&E, original magnification ×100).

Squamous cell carcinoma in situ classically appears as an erythematous hyperkeratotic papule or plaque on sun-exposed sites that can become crusted or ulcerated. Microscopically, squamous cell carcinoma in situ displays full-thickness disorderly maturation of keratinocytes. The keratinocytes exhibit nuclear pleomorphism. Atypical mitotic figures and dyskeratotic keratinocytes also can be seen throughout the full thickness of the epidermis (Figure 4).⁵

Figure 4. The epidermis is acanthotic and shows full-thickness disorderly maturation of keratinocytes, mitoses at different levels, and dyskeratotic cells in a squamous cell carcinoma in situ. Overlying parakeratosis also can be noted (H&E, original magnification ×100).

Verruca vulgaris (Figure 5) histologically demonstrates hyperkeratosis with tiers of parakeratosis, digitated epidermal hyperplasia, and dilated tortuous capillaries within the dermal papillae. At the edges of the lesion there often is inward turning of elongated rete ridges,^6,7 which can be thought of as the rete reaching out for a hug of sorts to spread the human papillomavirus infection. Although the surface of a trichilemmoma can bear resemblance to a verruca vulgaris, the remainder of the histologic features can be used to help differentiate these tumors. Additionally, there has been no evidence suggestive of a viral etiology for trichilemmomas.⁸

Figure 5. Compact hyperorthokeratosis with tiers of parakeratosis (arrow), digitated epidermal hyperplasia, hypergranulosis, vacuolated granular layer cells, and small blood vessels extending into the tips of the dermal papillae (asterisk) in the setting of a verruca vulgaris (H&E, original magnification ×100).

Warty dyskeratoma features an umbilicated papule, usually on the face, head, or neck, that is associated with a follicular unit. The papule shows a cup-shaped, keratin-filled invagination; suprabasilar clefting; and acantholytic dyskeratotic cells, which are features that are not seen in trichilemmomas (Figure 6).⁹

Figure 6. A cup-shaped invagination filled with cornified material and surrounded by slight epidermal hyperplasia in association with acantholytic dyskeratosis in a warty dyskeratoma (H&E, original magnifi-cation ×100).

Acknowledgment—The authors would like to thank Brandon Litzner, MD, St Louis, Missouri, for proofreading the manuscript.

Trichilemmomas are benign follicular neoplasms that exhibit differentiation toward the outer root sheath of the pilosebaceous follicular epithelium.¹ Trichilemmomas clinically present as individual or multiple, slowly growing, verrucous papules appearing most commonly on the face or neck. The lesions may coalesce to form small plaques. Although trichilemmomas typically are isolated, patients with multiple trichilemmomas require a cancer screening workup due to their association with Cowden disease, which results from a mutation in the phosphatase and tensin homolog tumor suppressor gene, PTEN.² An easy way to remember the association between trichilemmomas and Cowden disease is to alter the spelling to “trichile-moo-moo,” using the “moo moo” sound of an animal cow as a clue linking the tumor to Cowden disease.

Histologically, trichilemmomas exhibit a lobular epidermal downgrowth into the dermis (Figure 1). The surface of the lesion may be hyperkeratotic and somewhat papillomatous. Cells toward the center of the lobule are pale staining, periodic acid–Schiff positive, and diastase labile due to high levels of intracellular glycogen (Figure 2). Cells toward the periphery of the lobule usually appear basophilic with a palisading arrangement of the peripheral cells. The entire lobule is enclosed within an eosinophilic basement membrane that stains positively with periodic acid–Schiff (Figure 2).¹ Consistent with the tumor’s differentiation toward the outer root sheath of the hair follicle, trichilemmomas have been reported to express CD34 focally or diffusely.³

Figure 1. A lobular trichilemmoma composed of aggregates of epithelial cells extending from the epidermis into the dermis. The cells of the tumor are composed of squamoid cells showing variable glycogen vacuolation (pale-staining cytoplasm) and there is a surrounding prominent basement membrane (arrow)(H&E, original magnification ×40).

Figure 2. High-power magnification showing the pale-staining cells comprising a trichilemmoma (asterisk) as well as peripheral palisading of the cells at the periphery of the lesion and a thickened surrounding membrane (arrow)(H&E, original magnification ×200).

Similar to trichilemmoma, inverted follicular keratosis (IFK) commonly presents as a solitary asymptomatic papule on the face. Inverted follicular keratosis is a somewhat controversial entity, with some authorities arguing IFK is a variant of verruca vulgaris or seborrheic keratosis. Histologically, IFKs can be differentiated by the presence of squamous eddies (concentric layers of squamous cells in a whorled pattern), which are diagnostic, and central longitudinal crypts that contain keratin and are lined by squamous epithelium.⁴ Basaloid cells can be seen at the periphery of the tumors; however, IFKs lack an eosinophilic basement membrane surrounding the tumor (Figure 3).

Figure 3. Sections of a biopsy from an inverted follicular keratosis show an endophytic lesion with acanthosis consisting of fairly uniform squamous cells with eosinophilic cytoplasm. Numerous squamous eddies can be seen (H&E, original magnification ×100).

Squamous cell carcinoma in situ classically appears as an erythematous hyperkeratotic papule or plaque on sun-exposed sites that can become crusted or ulcerated. Microscopically, squamous cell carcinoma in situ displays full-thickness disorderly maturation of keratinocytes. The keratinocytes exhibit nuclear pleomorphism. Atypical mitotic figures and dyskeratotic keratinocytes also can be seen throughout the full thickness of the epidermis (Figure 4).⁵

Figure 4. The epidermis is acanthotic and shows full-thickness disorderly maturation of keratinocytes, mitoses at different levels, and dyskeratotic cells in a squamous cell carcinoma in situ. Overlying parakeratosis also can be noted (H&E, original magnification ×100).

Verruca vulgaris (Figure 5) histologically demonstrates hyperkeratosis with tiers of parakeratosis, digitated epidermal hyperplasia, and dilated tortuous capillaries within the dermal papillae. At the edges of the lesion there often is inward turning of elongated rete ridges,^6,7 which can be thought of as the rete reaching out for a hug of sorts to spread the human papillomavirus infection. Although the surface of a trichilemmoma can bear resemblance to a verruca vulgaris, the remainder of the histologic features can be used to help differentiate these tumors. Additionally, there has been no evidence suggestive of a viral etiology for trichilemmomas.⁸

Figure 5. Compact hyperorthokeratosis with tiers of parakeratosis (arrow), digitated epidermal hyperplasia, hypergranulosis, vacuolated granular layer cells, and small blood vessels extending into the tips of the dermal papillae (asterisk) in the setting of a verruca vulgaris (H&E, original magnification ×100).

Warty dyskeratoma features an umbilicated papule, usually on the face, head, or neck, that is associated with a follicular unit. The papule shows a cup-shaped, keratin-filled invagination; suprabasilar clefting; and acantholytic dyskeratotic cells, which are features that are not seen in trichilemmomas (Figure 6).⁹

Figure 6. A cup-shaped invagination filled with cornified material and surrounded by slight epidermal hyperplasia in association with acantholytic dyskeratosis in a warty dyskeratoma (H&E, original magnifi-cation ×100).

Acknowledgment—The authors would like to thank Brandon Litzner, MD, St Louis, Missouri, for proofreading the manuscript.

Trichilemmomas are benign follicular neoplasms that exhibit differentiation toward the outer root sheath of the pilosebaceous follicular epithelium.¹ Trichilemmomas clinically present as individual or multiple, slowly growing, verrucous papules appearing most commonly on the face or neck. The lesions may coalesce to form small plaques. Although trichilemmomas typically are isolated, patients with multiple trichilemmomas require a cancer screening workup due to their association with Cowden disease, which results from a mutation in the phosphatase and tensin homolog tumor suppressor gene, PTEN.² An easy way to remember the association between trichilemmomas and Cowden disease is to alter the spelling to “trichile-moo-moo,” using the “moo moo” sound of an animal cow as a clue linking the tumor to Cowden disease.

Histologically, trichilemmomas exhibit a lobular epidermal downgrowth into the dermis (Figure 1). The surface of the lesion may be hyperkeratotic and somewhat papillomatous. Cells toward the center of the lobule are pale staining, periodic acid–Schiff positive, and diastase labile due to high levels of intracellular glycogen (Figure 2). Cells toward the periphery of the lobule usually appear basophilic with a palisading arrangement of the peripheral cells. The entire lobule is enclosed within an eosinophilic basement membrane that stains positively with periodic acid–Schiff (Figure 2).¹ Consistent with the tumor’s differentiation toward the outer root sheath of the hair follicle, trichilemmomas have been reported to express CD34 focally or diffusely.³

Figure 1. A lobular trichilemmoma composed of aggregates of epithelial cells extending from the epidermis into the dermis. The cells of the tumor are composed of squamoid cells showing variable glycogen vacuolation (pale-staining cytoplasm) and there is a surrounding prominent basement membrane (arrow)(H&E, original magnification ×40).

Figure 2. High-power magnification showing the pale-staining cells comprising a trichilemmoma (asterisk) as well as peripheral palisading of the cells at the periphery of the lesion and a thickened surrounding membrane (arrow)(H&E, original magnification ×200).

Similar to trichilemmoma, inverted follicular keratosis (IFK) commonly presents as a solitary asymptomatic papule on the face. Inverted follicular keratosis is a somewhat controversial entity, with some authorities arguing IFK is a variant of verruca vulgaris or seborrheic keratosis. Histologically, IFKs can be differentiated by the presence of squamous eddies (concentric layers of squamous cells in a whorled pattern), which are diagnostic, and central longitudinal crypts that contain keratin and are lined by squamous epithelium.⁴ Basaloid cells can be seen at the periphery of the tumors; however, IFKs lack an eosinophilic basement membrane surrounding the tumor (Figure 3).

Figure 3. Sections of a biopsy from an inverted follicular keratosis show an endophytic lesion with acanthosis consisting of fairly uniform squamous cells with eosinophilic cytoplasm. Numerous squamous eddies can be seen (H&E, original magnification ×100).

Squamous cell carcinoma in situ classically appears as an erythematous hyperkeratotic papule or plaque on sun-exposed sites that can become crusted or ulcerated. Microscopically, squamous cell carcinoma in situ displays full-thickness disorderly maturation of keratinocytes. The keratinocytes exhibit nuclear pleomorphism. Atypical mitotic figures and dyskeratotic keratinocytes also can be seen throughout the full thickness of the epidermis (Figure 4).⁵

Figure 4. The epidermis is acanthotic and shows full-thickness disorderly maturation of keratinocytes, mitoses at different levels, and dyskeratotic cells in a squamous cell carcinoma in situ. Overlying parakeratosis also can be noted (H&E, original magnification ×100).

Verruca vulgaris (Figure 5) histologically demonstrates hyperkeratosis with tiers of parakeratosis, digitated epidermal hyperplasia, and dilated tortuous capillaries within the dermal papillae. At the edges of the lesion there often is inward turning of elongated rete ridges,^6,7 which can be thought of as the rete reaching out for a hug of sorts to spread the human papillomavirus infection. Although the surface of a trichilemmoma can bear resemblance to a verruca vulgaris, the remainder of the histologic features can be used to help differentiate these tumors. Additionally, there has been no evidence suggestive of a viral etiology for trichilemmomas.⁸

Figure 5. Compact hyperorthokeratosis with tiers of parakeratosis (arrow), digitated epidermal hyperplasia, hypergranulosis, vacuolated granular layer cells, and small blood vessels extending into the tips of the dermal papillae (asterisk) in the setting of a verruca vulgaris (H&E, original magnification ×100).

Warty dyskeratoma features an umbilicated papule, usually on the face, head, or neck, that is associated with a follicular unit. The papule shows a cup-shaped, keratin-filled invagination; suprabasilar clefting; and acantholytic dyskeratotic cells, which are features that are not seen in trichilemmomas (Figure 6).⁹

Figure 6. A cup-shaped invagination filled with cornified material and surrounded by slight epidermal hyperplasia in association with acantholytic dyskeratosis in a warty dyskeratoma (H&E, original magnifi-cation ×100).

Acknowledgment—The authors would like to thank Brandon Litzner, MD, St Louis, Missouri, for proofreading the manuscript.

Psychiatry is a field where the treatment of our disorders remains perplexing: We’re still trying to figure out if the best way to treat psychiatric conditions is through psychotherapy, with medications, or for more resistant conditions, by stimulating activity in the brain in several different ways.

The field of brain stimulation includes electroconvulsive therapy, as well as transcranial magnetic stimulation (TMS), direct transcranial current stimulation (tDCS), and deep brain stimulation (DBS), all of which are examples of treatments that are still just coming into their own.

In search of an update on brain stimulation, I met with Dr. Irving Reti, director of the Johns Hopkins Hospital Brain Stimulation Program and editor of “Brain Stimulation: Methodologies and Interventions” (Hoboken, N.J.: Wiley-Blackwell, 2015). We met at a Starbucks in Baltimore, and I’ll tell you that a one-on-one conversation with an expert is a wonderful way to learn about state-of-the-art treatments, the only downside being that Starbucks does not offer CME credit.

Dr. Reti, who went to medical school at the University of Sydney and speaks with a charming Australian accent, trained in psychiatry at Johns Hopkins, and then did a neuroscience fellowship.

“I’d just finished residency training, and I was giving ECT to rats. We were looking at the expression of immediate-early genes. At the same time, I started doing consults in the mood disorders clinic.”

In 2006, Dr. Reti took over as director of ECT at Hopkins, and that same year, Dr. Jimmy Potash got funding to study TMS. Dr. Potash has since moved to the University of Iowa, and Dr. Reti took over TMS administration at Hopkins. Dr. Reti was flattered to be approached by Wiley to edit “Brain Stimulation,” and he talked about how he was pleased with the final edition of the book.

“I ended up getting the top people to write the chapters, people like Sarah Lisanby, Michael Nitsche, John Rothwell, and Mark George. These are the leaders in the field of brain stimulation.”

I asked Dr. Reti to walk me through what was happening in each brain stimulation area.

“In ECT,” he said, “we know a lot more now about how both the settings and the anesthesia regimen affect the outcomes. We didn’t know this when I trained in the ’90s.” Dr. Reti estimated that he’s administered ECT to close to 2,000 patients.

TMS is done less often at Hopkins; he estimated that 10-20 patients receive the treatment, and each patient comes 30-40 times, with each session lasting 40 minutes.

“It’s better than medicine but not as effective as ECT. We’re seeing an efficacy rate around 50%-60%,” and he noted that some patients have trouble tolerating the procedure as the magnetic stimulation can be uncomfortable. “The TMS coil stimulates the scalp nerves and muscles immediately under the coil, which causes discomfort.” He noted that some patients need to premedicate with over-the-counter pain medicines.

“We’re also finding that low-frequency stimulation on the right can be helpful for anxiety,” Dr. Reti said.

He talked about treating patients with psychotherapy along with TMS. The brain changes are thought to increase the brain’s plasticity and perhaps make psychotherapy more effective.

“It’s being studied in drug treatment. You can show someone with an addiction stimuli to trigger cravings, and doing this with TMS may block the response,” he said.

He talked for a while about direct transcranial brain stimulation, which I was not very familiar with. Because it is being used to improve focus-playing video games, the equipment is not being marketed as a psychiatric treatment and doesn’t fall under the domain of the Food and Drug Administration.

“Kids are using it to improve their concentration and performance with video games; all you need is a 9-volt battery and some electrodes that are attached to the scalp. The kits cost about $250, but you can burn your scalp,” he said.

Dr. Reti referred me to an article in the New Yorker on tDCS, “Electrified: Adventures in transcranial direct-current stimulation” by Elif Batuman. He noted that there are studies in progress to look at therapeutic uses for tDCS, including one at Johns Hopkins where neuropsychologist David Schretlen is looking at improving cognition in schizophrenia. Dr. Reti is interested in seeing if tDCS might be helpful in decreasing self-injurious behaviors in autistic children, as ECT has been effective in severe cases. He noted that while ECT and TMS stimulate neurons in the brain to fire, tDCS changes the stimulation threshold without directly causing the neurons to discharge.

Finally, we talked a little about deep brain stimulation. Thin electrodes directly target nodes in brain circuits that can modulate the activity of those circuits. He noted that deep brain stimulation was being used at Johns Hopkins to treat Parkinson’s disease, and other centers have looked at its use for severe obsessive-compulsive disorder and treatment-resistant depression.

“We know that the response habituates; now they are trying on-demand DBS,” Dr. Reti noted.

So, although I got no continuing medical education credits, I did get to try a new Starbucks drink while having a very stimulating discussion on the latest convulsive and nonconvulsive psychiatric brain research.

Dr. Miller is a coauthor of “Shrink Rap: Three Psychiatrists Explain Their Work” (Baltimore: Johns Hopkins University Press, 2011).

Psychiatry is a field where the treatment of our disorders remains perplexing: We’re still trying to figure out if the best way to treat psychiatric conditions is through psychotherapy, with medications, or for more resistant conditions, by stimulating activity in the brain in several different ways.

The field of brain stimulation includes electroconvulsive therapy, as well as transcranial magnetic stimulation (TMS), direct transcranial current stimulation (tDCS), and deep brain stimulation (DBS), all of which are examples of treatments that are still just coming into their own.

In search of an update on brain stimulation, I met with Dr. Irving Reti, director of the Johns Hopkins Hospital Brain Stimulation Program and editor of “Brain Stimulation: Methodologies and Interventions” (Hoboken, N.J.: Wiley-Blackwell, 2015). We met at a Starbucks in Baltimore, and I’ll tell you that a one-on-one conversation with an expert is a wonderful way to learn about state-of-the-art treatments, the only downside being that Starbucks does not offer CME credit.

Dr. Reti, who went to medical school at the University of Sydney and speaks with a charming Australian accent, trained in psychiatry at Johns Hopkins, and then did a neuroscience fellowship.

“I’d just finished residency training, and I was giving ECT to rats. We were looking at the expression of immediate-early genes. At the same time, I started doing consults in the mood disorders clinic.”

In 2006, Dr. Reti took over as director of ECT at Hopkins, and that same year, Dr. Jimmy Potash got funding to study TMS. Dr. Potash has since moved to the University of Iowa, and Dr. Reti took over TMS administration at Hopkins. Dr. Reti was flattered to be approached by Wiley to edit “Brain Stimulation,” and he talked about how he was pleased with the final edition of the book.

“I ended up getting the top people to write the chapters, people like Sarah Lisanby, Michael Nitsche, John Rothwell, and Mark George. These are the leaders in the field of brain stimulation.”

I asked Dr. Reti to walk me through what was happening in each brain stimulation area.

“In ECT,” he said, “we know a lot more now about how both the settings and the anesthesia regimen affect the outcomes. We didn’t know this when I trained in the ’90s.” Dr. Reti estimated that he’s administered ECT to close to 2,000 patients.

TMS is done less often at Hopkins; he estimated that 10-20 patients receive the treatment, and each patient comes 30-40 times, with each session lasting 40 minutes.

“It’s better than medicine but not as effective as ECT. We’re seeing an efficacy rate around 50%-60%,” and he noted that some patients have trouble tolerating the procedure as the magnetic stimulation can be uncomfortable. “The TMS coil stimulates the scalp nerves and muscles immediately under the coil, which causes discomfort.” He noted that some patients need to premedicate with over-the-counter pain medicines.

“We’re also finding that low-frequency stimulation on the right can be helpful for anxiety,” Dr. Reti said.

He talked about treating patients with psychotherapy along with TMS. The brain changes are thought to increase the brain’s plasticity and perhaps make psychotherapy more effective.

“It’s being studied in drug treatment. You can show someone with an addiction stimuli to trigger cravings, and doing this with TMS may block the response,” he said.

He talked for a while about direct transcranial brain stimulation, which I was not very familiar with. Because it is being used to improve focus-playing video games, the equipment is not being marketed as a psychiatric treatment and doesn’t fall under the domain of the Food and Drug Administration.

“Kids are using it to improve their concentration and performance with video games; all you need is a 9-volt battery and some electrodes that are attached to the scalp. The kits cost about $250, but you can burn your scalp,” he said.

Dr. Reti referred me to an article in the New Yorker on tDCS, “Electrified: Adventures in transcranial direct-current stimulation” by Elif Batuman. He noted that there are studies in progress to look at therapeutic uses for tDCS, including one at Johns Hopkins where neuropsychologist David Schretlen is looking at improving cognition in schizophrenia. Dr. Reti is interested in seeing if tDCS might be helpful in decreasing self-injurious behaviors in autistic children, as ECT has been effective in severe cases. He noted that while ECT and TMS stimulate neurons in the brain to fire, tDCS changes the stimulation threshold without directly causing the neurons to discharge.

Finally, we talked a little about deep brain stimulation. Thin electrodes directly target nodes in brain circuits that can modulate the activity of those circuits. He noted that deep brain stimulation was being used at Johns Hopkins to treat Parkinson’s disease, and other centers have looked at its use for severe obsessive-compulsive disorder and treatment-resistant depression.

“We know that the response habituates; now they are trying on-demand DBS,” Dr. Reti noted.

So, although I got no continuing medical education credits, I did get to try a new Starbucks drink while having a very stimulating discussion on the latest convulsive and nonconvulsive psychiatric brain research.

Dr. Miller is a coauthor of “Shrink Rap: Three Psychiatrists Explain Their Work” (Baltimore: Johns Hopkins University Press, 2011).

Psychiatry is a field where the treatment of our disorders remains perplexing: We’re still trying to figure out if the best way to treat psychiatric conditions is through psychotherapy, with medications, or for more resistant conditions, by stimulating activity in the brain in several different ways.

The field of brain stimulation includes electroconvulsive therapy, as well as transcranial magnetic stimulation (TMS), direct transcranial current stimulation (tDCS), and deep brain stimulation (DBS), all of which are examples of treatments that are still just coming into their own.

In search of an update on brain stimulation, I met with Dr. Irving Reti, director of the Johns Hopkins Hospital Brain Stimulation Program and editor of “Brain Stimulation: Methodologies and Interventions” (Hoboken, N.J.: Wiley-Blackwell, 2015). We met at a Starbucks in Baltimore, and I’ll tell you that a one-on-one conversation with an expert is a wonderful way to learn about state-of-the-art treatments, the only downside being that Starbucks does not offer CME credit.

Dr. Reti, who went to medical school at the University of Sydney and speaks with a charming Australian accent, trained in psychiatry at Johns Hopkins, and then did a neuroscience fellowship.

“I’d just finished residency training, and I was giving ECT to rats. We were looking at the expression of immediate-early genes. At the same time, I started doing consults in the mood disorders clinic.”

In 2006, Dr. Reti took over as director of ECT at Hopkins, and that same year, Dr. Jimmy Potash got funding to study TMS. Dr. Potash has since moved to the University of Iowa, and Dr. Reti took over TMS administration at Hopkins. Dr. Reti was flattered to be approached by Wiley to edit “Brain Stimulation,” and he talked about how he was pleased with the final edition of the book.

“I ended up getting the top people to write the chapters, people like Sarah Lisanby, Michael Nitsche, John Rothwell, and Mark George. These are the leaders in the field of brain stimulation.”

I asked Dr. Reti to walk me through what was happening in each brain stimulation area.

“In ECT,” he said, “we know a lot more now about how both the settings and the anesthesia regimen affect the outcomes. We didn’t know this when I trained in the ’90s.” Dr. Reti estimated that he’s administered ECT to close to 2,000 patients.

TMS is done less often at Hopkins; he estimated that 10-20 patients receive the treatment, and each patient comes 30-40 times, with each session lasting 40 minutes.

“It’s better than medicine but not as effective as ECT. We’re seeing an efficacy rate around 50%-60%,” and he noted that some patients have trouble tolerating the procedure as the magnetic stimulation can be uncomfortable. “The TMS coil stimulates the scalp nerves and muscles immediately under the coil, which causes discomfort.” He noted that some patients need to premedicate with over-the-counter pain medicines.

“We’re also finding that low-frequency stimulation on the right can be helpful for anxiety,” Dr. Reti said.

He talked about treating patients with psychotherapy along with TMS. The brain changes are thought to increase the brain’s plasticity and perhaps make psychotherapy more effective.

“It’s being studied in drug treatment. You can show someone with an addiction stimuli to trigger cravings, and doing this with TMS may block the response,” he said.

He talked for a while about direct transcranial brain stimulation, which I was not very familiar with. Because it is being used to improve focus-playing video games, the equipment is not being marketed as a psychiatric treatment and doesn’t fall under the domain of the Food and Drug Administration.

“Kids are using it to improve their concentration and performance with video games; all you need is a 9-volt battery and some electrodes that are attached to the scalp. The kits cost about $250, but you can burn your scalp,” he said.

Dr. Reti referred me to an article in the New Yorker on tDCS, “Electrified: Adventures in transcranial direct-current stimulation” by Elif Batuman. He noted that there are studies in progress to look at therapeutic uses for tDCS, including one at Johns Hopkins where neuropsychologist David Schretlen is looking at improving cognition in schizophrenia. Dr. Reti is interested in seeing if tDCS might be helpful in decreasing self-injurious behaviors in autistic children, as ECT has been effective in severe cases. He noted that while ECT and TMS stimulate neurons in the brain to fire, tDCS changes the stimulation threshold without directly causing the neurons to discharge.

Finally, we talked a little about deep brain stimulation. Thin electrodes directly target nodes in brain circuits that can modulate the activity of those circuits. He noted that deep brain stimulation was being used at Johns Hopkins to treat Parkinson’s disease, and other centers have looked at its use for severe obsessive-compulsive disorder and treatment-resistant depression.

“We know that the response habituates; now they are trying on-demand DBS,” Dr. Reti noted.

So, although I got no continuing medical education credits, I did get to try a new Starbucks drink while having a very stimulating discussion on the latest convulsive and nonconvulsive psychiatric brain research.

Dr. Miller is a coauthor of “Shrink Rap: Three Psychiatrists Explain Their Work” (Baltimore: Johns Hopkins University Press, 2011).

PARK CITY, UTAH – At the annual meeting of the Pacific Dermatologic Association, Dr. Sancy A. Leachman offered a top 10 list of new agents and technologies for the treatment of vitiligo.

No. 10: Ultraviolet A1 (UVA1) phototherapy

Dr. Harvey Lui at the University of British Columbia in Vancouver is leading a phase II trial to evaluate the potential for UVA1 to induce repigmentation within vitiligo patches and to assess the side effect profile of the treatment. “I think it might work,” said Dr. Leachman, professor and chair of dermatology at Oregon Health & Science University (OHSU), Portland.

No. 9: Ginkgo biloba

The use of ginko biloba 40-60 mg 2-3 times per day, 10 minutes before a meal, was mentioned in a Cochrane Review of vitiligo treatments published on Feb. 24, 2015. “I think I’m going to give this a try in people who have failed other treatments and see if I can get some response,” Dr. Leachman said.

No. 8: Red light

Dr. Lui is leading a randomized phase II trial of low-intensity and high-intensity red light versus no treatment for vitiligo patches. Treatments will be given twice weekly for 10 weeks, with follow-up assessments at 4, 8, and 12 weeks post treatment.

No. 7: Micrografting

A novel suction blister device known as the CelluTome epidermal harvesting system uses heat and slight vacuum pressure to harvest healthy epidermal skin tissue without damaging the donor site. Dr. Leachman characterized the technology as “semiautomating the process of suction graft transplantation.”

No. 6: The ReCell device

Manufactured by Avita Medical, this investigational autologous cell harvesting device is used after CO2 abrasion and enables clinicians to create regenerative epithelial suspension with a small sample of the patient’s skin. A phase IV trial in the Netherlands is underway to assess the efficacy and safety of autologous epidermal cell suspension grafting with the ReCell device after CO₂ laser abrasion, compared with CO₂ laser abrasion alone and no treatment, in patients with piebaldism and stable vitiligo.

Courtesy Dr. Sancy A. Leachman

No. 5: Topical Photocil

In a pilot study sponsored by Applied Biology, researchers are enrolling patients with vitiligo to assess the safety and efficacy of Photocil. The primary outcome measure is the Vitiligo Area Severity Index (VASI). “When this cream is activated by sunlight, it degrades into narrow-band and UVB light, so you can put a topical cream on that will administer narrow-band UVB only in that spot,” said Dr. Leachman, who is also director of OHSU’s Knight Melanoma Research Program. “That’s amazing to me.”

No. 4: Afamelanotide

This is an analogue of a melanocyte-stimulating hormone. A randomized study conducted at two academic medical centers found that the combination of afamelanotide implant and narrow-band UVB phototherapy resulted in statistically superior and faster repigmentation, compared with narrow-band UVB monotherapy (JAMA Dermatol. 2015 Jan;151(1):42-50).

No. 3: Abatacept (Orencia)

This is a soluble fusion protein consisting of human cytotoxic T-lymphocyte–associated antigen 4 (CTLA4), which prevents T-cell activation. A phase I trial is underway at Brigham and Women’s Hospital in Boston to determine if weekly self-injections of the agent lead to clinical improvements of vitiligo lesions. The primary outcome measure is change in repigmentation with abatacept therapy based on the VASI score.

No. 2. Simvastatin

The notion of its use is based on STAT1 inhibition reducing interferon-gamma–dependent activation of CD8-positive T cells, according to Dr. Leachman. The concept has been successful in a mouse model, and a study in humans was recently completed by Dr. John Harris at the University of Massachusetts, Worcester. “What we have is the ability to apply an existing drug (Simvastatin) to the process and see if it works,” she said. “Wouldn’t it be cool if we could give a statin and improve vitiligo?”

No 1: Tofacitinib

This is a Janus kinase inhibitor commonly used for rheumatoid arthritis. According to Dr. Leachman, Janus kinase inhibition prevents STAT activation, “which prevents [interferon]-gamma production, which reduces activation of CD8-positive T cells via CXCL10 binding to CXCR3,” she said. A case report demonstrating its efficacy in a 53-year-old patient was recently published in JAMA Dermatology by Dr. Brett A. King and Dr. Brittany Craiglow, dermatologists at Yale School of Medicine, New Haven, Conn. “I’m hopeful that this [agent] will be made into a topical cream because these drugs do have substantial side effects,” Dr. Leachman said.

Dr. Leachman disclosed that she is a member of the medical and scientific advisory board for Myriad Genetics Laboratory. She has also participated in an advisory board meeting for Castle Biosciences and has participated in the DecisionDx registry.

dbrunk@frontlinemedcom.com

PARK CITY, UTAH – At the annual meeting of the Pacific Dermatologic Association, Dr. Sancy A. Leachman offered a top 10 list of new agents and technologies for the treatment of vitiligo.

No. 10: Ultraviolet A1 (UVA1) phototherapy

Dr. Harvey Lui at the University of British Columbia in Vancouver is leading a phase II trial to evaluate the potential for UVA1 to induce repigmentation within vitiligo patches and to assess the side effect profile of the treatment. “I think it might work,” said Dr. Leachman, professor and chair of dermatology at Oregon Health & Science University (OHSU), Portland.

No. 9: Ginkgo biloba

The use of ginko biloba 40-60 mg 2-3 times per day, 10 minutes before a meal, was mentioned in a Cochrane Review of vitiligo treatments published on Feb. 24, 2015. “I think I’m going to give this a try in people who have failed other treatments and see if I can get some response,” Dr. Leachman said.

No. 8: Red light

Dr. Lui is leading a randomized phase II trial of low-intensity and high-intensity red light versus no treatment for vitiligo patches. Treatments will be given twice weekly for 10 weeks, with follow-up assessments at 4, 8, and 12 weeks post treatment.

No. 7: Micrografting

A novel suction blister device known as the CelluTome epidermal harvesting system uses heat and slight vacuum pressure to harvest healthy epidermal skin tissue without damaging the donor site. Dr. Leachman characterized the technology as “semiautomating the process of suction graft transplantation.”

No. 6: The ReCell device

Manufactured by Avita Medical, this investigational autologous cell harvesting device is used after CO2 abrasion and enables clinicians to create regenerative epithelial suspension with a small sample of the patient’s skin. A phase IV trial in the Netherlands is underway to assess the efficacy and safety of autologous epidermal cell suspension grafting with the ReCell device after CO₂ laser abrasion, compared with CO₂ laser abrasion alone and no treatment, in patients with piebaldism and stable vitiligo.

Courtesy Dr. Sancy A. Leachman

No. 5: Topical Photocil

In a pilot study sponsored by Applied Biology, researchers are enrolling patients with vitiligo to assess the safety and efficacy of Photocil. The primary outcome measure is the Vitiligo Area Severity Index (VASI). “When this cream is activated by sunlight, it degrades into narrow-band and UVB light, so you can put a topical cream on that will administer narrow-band UVB only in that spot,” said Dr. Leachman, who is also director of OHSU’s Knight Melanoma Research Program. “That’s amazing to me.”

No. 4: Afamelanotide

This is an analogue of a melanocyte-stimulating hormone. A randomized study conducted at two academic medical centers found that the combination of afamelanotide implant and narrow-band UVB phototherapy resulted in statistically superior and faster repigmentation, compared with narrow-band UVB monotherapy (JAMA Dermatol. 2015 Jan;151(1):42-50).

No. 3: Abatacept (Orencia)

This is a soluble fusion protein consisting of human cytotoxic T-lymphocyte–associated antigen 4 (CTLA4), which prevents T-cell activation. A phase I trial is underway at Brigham and Women’s Hospital in Boston to determine if weekly self-injections of the agent lead to clinical improvements of vitiligo lesions. The primary outcome measure is change in repigmentation with abatacept therapy based on the VASI score.

No. 2. Simvastatin

The notion of its use is based on STAT1 inhibition reducing interferon-gamma–dependent activation of CD8-positive T cells, according to Dr. Leachman. The concept has been successful in a mouse model, and a study in humans was recently completed by Dr. John Harris at the University of Massachusetts, Worcester. “What we have is the ability to apply an existing drug (Simvastatin) to the process and see if it works,” she said. “Wouldn’t it be cool if we could give a statin and improve vitiligo?”

No 1: Tofacitinib

This is a Janus kinase inhibitor commonly used for rheumatoid arthritis. According to Dr. Leachman, Janus kinase inhibition prevents STAT activation, “which prevents [interferon]-gamma production, which reduces activation of CD8-positive T cells via CXCL10 binding to CXCR3,” she said. A case report demonstrating its efficacy in a 53-year-old patient was recently published in JAMA Dermatology by Dr. Brett A. King and Dr. Brittany Craiglow, dermatologists at Yale School of Medicine, New Haven, Conn. “I’m hopeful that this [agent] will be made into a topical cream because these drugs do have substantial side effects,” Dr. Leachman said.

Dr. Leachman disclosed that she is a member of the medical and scientific advisory board for Myriad Genetics Laboratory. She has also participated in an advisory board meeting for Castle Biosciences and has participated in the DecisionDx registry.

dbrunk@frontlinemedcom.com

PARK CITY, UTAH – At the annual meeting of the Pacific Dermatologic Association, Dr. Sancy A. Leachman offered a top 10 list of new agents and technologies for the treatment of vitiligo.

No. 10: Ultraviolet A1 (UVA1) phototherapy

Dr. Harvey Lui at the University of British Columbia in Vancouver is leading a phase II trial to evaluate the potential for UVA1 to induce repigmentation within vitiligo patches and to assess the side effect profile of the treatment. “I think it might work,” said Dr. Leachman, professor and chair of dermatology at Oregon Health & Science University (OHSU), Portland.

No. 9: Ginkgo biloba

The use of ginko biloba 40-60 mg 2-3 times per day, 10 minutes before a meal, was mentioned in a Cochrane Review of vitiligo treatments published on Feb. 24, 2015. “I think I’m going to give this a try in people who have failed other treatments and see if I can get some response,” Dr. Leachman said.

No. 8: Red light

Dr. Lui is leading a randomized phase II trial of low-intensity and high-intensity red light versus no treatment for vitiligo patches. Treatments will be given twice weekly for 10 weeks, with follow-up assessments at 4, 8, and 12 weeks post treatment.

No. 7: Micrografting

A novel suction blister device known as the CelluTome epidermal harvesting system uses heat and slight vacuum pressure to harvest healthy epidermal skin tissue without damaging the donor site. Dr. Leachman characterized the technology as “semiautomating the process of suction graft transplantation.”

No. 6: The ReCell device

Manufactured by Avita Medical, this investigational autologous cell harvesting device is used after CO2 abrasion and enables clinicians to create regenerative epithelial suspension with a small sample of the patient’s skin. A phase IV trial in the Netherlands is underway to assess the efficacy and safety of autologous epidermal cell suspension grafting with the ReCell device after CO₂ laser abrasion, compared with CO₂ laser abrasion alone and no treatment, in patients with piebaldism and stable vitiligo.

Courtesy Dr. Sancy A. Leachman

No. 5: Topical Photocil

In a pilot study sponsored by Applied Biology, researchers are enrolling patients with vitiligo to assess the safety and efficacy of Photocil. The primary outcome measure is the Vitiligo Area Severity Index (VASI). “When this cream is activated by sunlight, it degrades into narrow-band and UVB light, so you can put a topical cream on that will administer narrow-band UVB only in that spot,” said Dr. Leachman, who is also director of OHSU’s Knight Melanoma Research Program. “That’s amazing to me.”

No. 4: Afamelanotide

This is an analogue of a melanocyte-stimulating hormone. A randomized study conducted at two academic medical centers found that the combination of afamelanotide implant and narrow-band UVB phototherapy resulted in statistically superior and faster repigmentation, compared with narrow-band UVB monotherapy (JAMA Dermatol. 2015 Jan;151(1):42-50).

No. 3: Abatacept (Orencia)

This is a soluble fusion protein consisting of human cytotoxic T-lymphocyte–associated antigen 4 (CTLA4), which prevents T-cell activation. A phase I trial is underway at Brigham and Women’s Hospital in Boston to determine if weekly self-injections of the agent lead to clinical improvements of vitiligo lesions. The primary outcome measure is change in repigmentation with abatacept therapy based on the VASI score.

No. 2. Simvastatin

The notion of its use is based on STAT1 inhibition reducing interferon-gamma–dependent activation of CD8-positive T cells, according to Dr. Leachman. The concept has been successful in a mouse model, and a study in humans was recently completed by Dr. John Harris at the University of Massachusetts, Worcester. “What we have is the ability to apply an existing drug (Simvastatin) to the process and see if it works,” she said. “Wouldn’t it be cool if we could give a statin and improve vitiligo?”

No 1: Tofacitinib

This is a Janus kinase inhibitor commonly used for rheumatoid arthritis. According to Dr. Leachman, Janus kinase inhibition prevents STAT activation, “which prevents [interferon]-gamma production, which reduces activation of CD8-positive T cells via CXCL10 binding to CXCR3,” she said. A case report demonstrating its efficacy in a 53-year-old patient was recently published in JAMA Dermatology by Dr. Brett A. King and Dr. Brittany Craiglow, dermatologists at Yale School of Medicine, New Haven, Conn. “I’m hopeful that this [agent] will be made into a topical cream because these drugs do have substantial side effects,” Dr. Leachman said.

Dr. Leachman disclosed that she is a member of the medical and scientific advisory board for Myriad Genetics Laboratory. She has also participated in an advisory board meeting for Castle Biosciences and has participated in the DecisionDx registry.

dbrunk@frontlinemedcom.com

Hospitalists who presented RIV posters at HM15 talk about their projects. Dr. Brian Poustinchian worked on a bedside rounding study at Midwestern University in Illinois, and Dr. Jennifer Pascoe worked on a poster about patients leaving the hospital against medical advice, focusing on a case of her own at the University of Rochester.

Hospitalists who presented RIV posters at HM15 talk about their projects. Dr. Brian Poustinchian worked on a bedside rounding study at Midwestern University in Illinois, and Dr. Jennifer Pascoe worked on a poster about patients leaving the hospital against medical advice, focusing on a case of her own at the University of Rochester.

Hospitalists who presented RIV posters at HM15 talk about their projects. Dr. Brian Poustinchian worked on a bedside rounding study at Midwestern University in Illinois, and Dr. Jennifer Pascoe worked on a poster about patients leaving the hospital against medical advice, focusing on a case of her own at the University of Rochester.