Mangifera indica (mango) is a member of the Anacardiaceae family with a tradition of use as a medicinal plant. Mango extracts have been characterized as exhibiting antioxidant, anti-inflammatory, analgesic, and immunomodulatory activities (Photodermatol. Photoimmunol. Photomed. 2013;29:84-9; Drug Chem. Toxicol. 2009;32:53-8). Mango is grown in more than 100 countries, primarily in Asia, in tropical as well as subtropical regions (Molecules 2014;19:17107-29). Mango stem bark and leaves have been used in traditional medicine to treat anemia, cutaneous infections, diabetes, diarrhea, scabies, syphilis, and malignant tumors (Pharmacol. Res. 2007;55:351-8). Polyphenols and carotenoids are among the phytonutrients identified as responsible for the biologic activity of mango (Photodermatol. Photoimmunol. Photomed. 2013;29:84-9).

Courtesy Wikimedia Commons/Roei.tabak /Creative Commons License

Various biologic activities and traditional uses

Ojewole investigated the anti-inflammatory, analgesic, and antidiabetic activity of M. indica stem bark aqueous extract in rats and mice in 2005. In mice, mango extract dose-dependently delivered significant analgesic effects against thermally and chemically-generated pain. The investigators attributed the observed salutary effects of the plant to its constituent polyphenolics, flavonoids, triterpenoids, and mangiferin. They also noted that their findings support the folkloric uses of the plant for treating arthritic and other inflammatory conditions, as well as type 2 diabetes (Methods Find. Exp. Clin. Pharmacol. 2005;27:547-54).

Another important constituent of mango (also found in olive, strawberry, fig, and various medicinal herbs) is the triterpene lupeol, which has been characterized as exhibiting potent antioxidant, antimutagenic, anti-inflammatory, and antiarthritic activity (Oncogene 2004;23:5203-14). A 2014 study by Sahu et al. also showed that M. indica leaves display some antityrosinase activity, though not as strongly as other medicinal plants, such as Emblica officinalis (Pak. J. Biol. Sci. 2014;17:146-50).

Anticancer, antioxidant, and antiphotoaging activity

In 2004, Saleem et al. demonstrated that topically applied lupeol exhibited anti–tumor-promoting effects in a CD-1 mouse skin tumorigenesis model. Pretreatment with the mango constituent time- and dose-dependently inhibited multiple 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-mediated increases in edema, hyperplasia, epidermal ornithine decarboxylase (ODC) activity, as well as protein expression of ODC, cyclooxygenase 2 (COX-2) and nitric oxide synthase. Pretreated animals also experienced significantly lower tumor incidence and tumor body burden as well as a significant delay in tumor latency period. The researchers concluded that lupeol exerts anti–skin tumor promoting effects on CD-1 mice (Oncogene 2004;23:5203-14).

Three years later, Núñez-Sellés et al. reported that a mango stem bark extract (Vimang) developed in Cuba exhibited antioxidant, analgesic, anti-inflammatory, and immunomodulating activity in basic, preclinical, and clinical studies (Pharmacol. Res. 2007;55:351-8).

A 2009 toxicological analysis of Vimang, which has been formulated into tablets, creams, capsules, syrup, vaginal oval, and suppositories for various applications, revealed via irritant tests conducted on rabbits that the topical formulation was not irritating to the skin, generally, with minimal irritancy noted after vaginal application. No adverse effects were reported (Drug Chem. Toxicol. 2009;32:53-8).

In 2012, Li et al. discovered norathyriol (1,3,6,7-tetrahydroxy-9H-xanthen-9-one), a plant-derived chemopreventive metabolite of mangiferin, found in mango, Hypericum elegans, and Tripterospermum lanceolatum. They found that norathyriol significantly inhibited solar UV-induced skin carcinogenesis in mouse models. In vitro investigations revealed that the compound suppressed cell growth in mouse skin epidermal JB6 P+ cells at the level of G2-M phase arrest. The investigators concluded that this newly identified substance appears to act as a safe chemopreventive agent against UV-induced skin cancer (Cancer Res. 2012;72:260-70).

A year later, Song et al. assessed the protective effects of orally administered mango extract against UVB-induced cutaneous aging in HR-1 hairless male mice. The animals were divided into control, UVB-treated vehicle, and UVB-treated mango extract groups. The researchers found that mango extract significantly suppressed the increase in epidermal thickness and hypertrophy indicative of UVB treatment, with mean length of wrinkles significantly lower in the mango group compared with the UVB-treated vehicle group. Treatment with mango extract also led to a significant increase in collagen bundles in animals treated with UVB. The authors concluded that mango extract displayed antiphotoaging properties in hairless mice exposed to UVB (Photodermatol. Photoimmunol. Photomed. 2013;29:84-9).

Further, a 2014 in vitro study revealed that extracts of Helicanthus elastica growing on M. indica exhibited antioxidant activity. H. elastica is a hemiparasite that often grows on mango trees in India and is known to be a rich source of phenolic substances (J. Tradit. Complement. Med. 2014;4:285-8).

Topical delivery

Mandawgade and Patravale developed a mango butter skin care formulation in 2008 that was used to test skin repair in rat excision and incision wound models. A healing response was noted in both animal models. The formulation also was found to be effective in achieving complete repair of worn and cracked skin on the feet of all human volunteers in the study. The investigators concluded that the mango butter preparation delivers superlative emolliency and warrants consideration as an excipient agent in cosmeceutical products (Indian J. Pharm. Sci. 2008;70:539-42).

It is worth noting that cases of “mango dermatitis” (allergic contact dermatitis to the sap or skin of M. indica), manifesting in urticaria and eczematous rashes, have been reported (Australas. J. Dermatol. 1996;37:59-60; Int. J. Dermatol. 2004;43:195-6).

In 2014, Leanpolchareanchai et al. developed a microemulsion system containing Thai mango seed kernel extract that displayed strong skin enhancement results in ex vivo skin permeation studies (penetrating skin layers up to 60-fold higher than controls) and physicochemical stability over 6 months (Drug Chem. Toxicol. 2009;32:53-8). Thai mango seed kernel extract had previously been shown to exhibit anti–methicillin-resistant Staphylococcus aureus and antityrosinase characteristics, as well as strong free radical scavenging, antioxidant, anti-inflammatory, and hepatoprotective activities.(Molecules 2014;19:17107-29).

Conclusion

Evidence on the cutaneous applications of mango is emerging, but does not have a significant track record. That said, this fruit has long been used in traditional medicine for a range of indications, including skin disorders. Much more research is necessary, however, to ascertain how beneficial this fruit and its extracts may be. At the very least, there are few reports of adverse events associated with topical application.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in the Design District in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote the textbook “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and a book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). She has contributed to the Cosmeceutical Critique column in Dermatology News since January 2001. Her latest book, “Cosmeceuticals and Cosmetic Ingredients,” was published in November 2014. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Evolus, Galderma, GlaxoSmithKline, Kythera, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Topix Pharmaceuticals, and Unilever.

Mangifera indica (mango) is a member of the Anacardiaceae family with a tradition of use as a medicinal plant. Mango extracts have been characterized as exhibiting antioxidant, anti-inflammatory, analgesic, and immunomodulatory activities (Photodermatol. Photoimmunol. Photomed. 2013;29:84-9; Drug Chem. Toxicol. 2009;32:53-8). Mango is grown in more than 100 countries, primarily in Asia, in tropical as well as subtropical regions (Molecules 2014;19:17107-29). Mango stem bark and leaves have been used in traditional medicine to treat anemia, cutaneous infections, diabetes, diarrhea, scabies, syphilis, and malignant tumors (Pharmacol. Res. 2007;55:351-8). Polyphenols and carotenoids are among the phytonutrients identified as responsible for the biologic activity of mango (Photodermatol. Photoimmunol. Photomed. 2013;29:84-9).

Courtesy Wikimedia Commons/Roei.tabak /Creative Commons License

Various biologic activities and traditional uses

Ojewole investigated the anti-inflammatory, analgesic, and antidiabetic activity of M. indica stem bark aqueous extract in rats and mice in 2005. In mice, mango extract dose-dependently delivered significant analgesic effects against thermally and chemically-generated pain. The investigators attributed the observed salutary effects of the plant to its constituent polyphenolics, flavonoids, triterpenoids, and mangiferin. They also noted that their findings support the folkloric uses of the plant for treating arthritic and other inflammatory conditions, as well as type 2 diabetes (Methods Find. Exp. Clin. Pharmacol. 2005;27:547-54).

Another important constituent of mango (also found in olive, strawberry, fig, and various medicinal herbs) is the triterpene lupeol, which has been characterized as exhibiting potent antioxidant, antimutagenic, anti-inflammatory, and antiarthritic activity (Oncogene 2004;23:5203-14). A 2014 study by Sahu et al. also showed that M. indica leaves display some antityrosinase activity, though not as strongly as other medicinal plants, such as Emblica officinalis (Pak. J. Biol. Sci. 2014;17:146-50).

Anticancer, antioxidant, and antiphotoaging activity

In 2004, Saleem et al. demonstrated that topically applied lupeol exhibited anti–tumor-promoting effects in a CD-1 mouse skin tumorigenesis model. Pretreatment with the mango constituent time- and dose-dependently inhibited multiple 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-mediated increases in edema, hyperplasia, epidermal ornithine decarboxylase (ODC) activity, as well as protein expression of ODC, cyclooxygenase 2 (COX-2) and nitric oxide synthase. Pretreated animals also experienced significantly lower tumor incidence and tumor body burden as well as a significant delay in tumor latency period. The researchers concluded that lupeol exerts anti–skin tumor promoting effects on CD-1 mice (Oncogene 2004;23:5203-14).

Three years later, Núñez-Sellés et al. reported that a mango stem bark extract (Vimang) developed in Cuba exhibited antioxidant, analgesic, anti-inflammatory, and immunomodulating activity in basic, preclinical, and clinical studies (Pharmacol. Res. 2007;55:351-8).

A 2009 toxicological analysis of Vimang, which has been formulated into tablets, creams, capsules, syrup, vaginal oval, and suppositories for various applications, revealed via irritant tests conducted on rabbits that the topical formulation was not irritating to the skin, generally, with minimal irritancy noted after vaginal application. No adverse effects were reported (Drug Chem. Toxicol. 2009;32:53-8).

In 2012, Li et al. discovered norathyriol (1,3,6,7-tetrahydroxy-9H-xanthen-9-one), a plant-derived chemopreventive metabolite of mangiferin, found in mango, Hypericum elegans, and Tripterospermum lanceolatum. They found that norathyriol significantly inhibited solar UV-induced skin carcinogenesis in mouse models. In vitro investigations revealed that the compound suppressed cell growth in mouse skin epidermal JB6 P+ cells at the level of G2-M phase arrest. The investigators concluded that this newly identified substance appears to act as a safe chemopreventive agent against UV-induced skin cancer (Cancer Res. 2012;72:260-70).

A year later, Song et al. assessed the protective effects of orally administered mango extract against UVB-induced cutaneous aging in HR-1 hairless male mice. The animals were divided into control, UVB-treated vehicle, and UVB-treated mango extract groups. The researchers found that mango extract significantly suppressed the increase in epidermal thickness and hypertrophy indicative of UVB treatment, with mean length of wrinkles significantly lower in the mango group compared with the UVB-treated vehicle group. Treatment with mango extract also led to a significant increase in collagen bundles in animals treated with UVB. The authors concluded that mango extract displayed antiphotoaging properties in hairless mice exposed to UVB (Photodermatol. Photoimmunol. Photomed. 2013;29:84-9).

Further, a 2014 in vitro study revealed that extracts of Helicanthus elastica growing on M. indica exhibited antioxidant activity. H. elastica is a hemiparasite that often grows on mango trees in India and is known to be a rich source of phenolic substances (J. Tradit. Complement. Med. 2014;4:285-8).

Topical delivery

Mandawgade and Patravale developed a mango butter skin care formulation in 2008 that was used to test skin repair in rat excision and incision wound models. A healing response was noted in both animal models. The formulation also was found to be effective in achieving complete repair of worn and cracked skin on the feet of all human volunteers in the study. The investigators concluded that the mango butter preparation delivers superlative emolliency and warrants consideration as an excipient agent in cosmeceutical products (Indian J. Pharm. Sci. 2008;70:539-42).

It is worth noting that cases of “mango dermatitis” (allergic contact dermatitis to the sap or skin of M. indica), manifesting in urticaria and eczematous rashes, have been reported (Australas. J. Dermatol. 1996;37:59-60; Int. J. Dermatol. 2004;43:195-6).

In 2014, Leanpolchareanchai et al. developed a microemulsion system containing Thai mango seed kernel extract that displayed strong skin enhancement results in ex vivo skin permeation studies (penetrating skin layers up to 60-fold higher than controls) and physicochemical stability over 6 months (Drug Chem. Toxicol. 2009;32:53-8). Thai mango seed kernel extract had previously been shown to exhibit anti–methicillin-resistant Staphylococcus aureus and antityrosinase characteristics, as well as strong free radical scavenging, antioxidant, anti-inflammatory, and hepatoprotective activities.(Molecules 2014;19:17107-29).

Conclusion

Evidence on the cutaneous applications of mango is emerging, but does not have a significant track record. That said, this fruit has long been used in traditional medicine for a range of indications, including skin disorders. Much more research is necessary, however, to ascertain how beneficial this fruit and its extracts may be. At the very least, there are few reports of adverse events associated with topical application.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in the Design District in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote the textbook “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and a book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). She has contributed to the Cosmeceutical Critique column in Dermatology News since January 2001. Her latest book, “Cosmeceuticals and Cosmetic Ingredients,” was published in November 2014. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Evolus, Galderma, GlaxoSmithKline, Kythera, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Topix Pharmaceuticals, and Unilever.

Mangifera indica (mango) is a member of the Anacardiaceae family with a tradition of use as a medicinal plant. Mango extracts have been characterized as exhibiting antioxidant, anti-inflammatory, analgesic, and immunomodulatory activities (Photodermatol. Photoimmunol. Photomed. 2013;29:84-9; Drug Chem. Toxicol. 2009;32:53-8). Mango is grown in more than 100 countries, primarily in Asia, in tropical as well as subtropical regions (Molecules 2014;19:17107-29). Mango stem bark and leaves have been used in traditional medicine to treat anemia, cutaneous infections, diabetes, diarrhea, scabies, syphilis, and malignant tumors (Pharmacol. Res. 2007;55:351-8). Polyphenols and carotenoids are among the phytonutrients identified as responsible for the biologic activity of mango (Photodermatol. Photoimmunol. Photomed. 2013;29:84-9).

Courtesy Wikimedia Commons/Roei.tabak /Creative Commons License

Various biologic activities and traditional uses

Ojewole investigated the anti-inflammatory, analgesic, and antidiabetic activity of M. indica stem bark aqueous extract in rats and mice in 2005. In mice, mango extract dose-dependently delivered significant analgesic effects against thermally and chemically-generated pain. The investigators attributed the observed salutary effects of the plant to its constituent polyphenolics, flavonoids, triterpenoids, and mangiferin. They also noted that their findings support the folkloric uses of the plant for treating arthritic and other inflammatory conditions, as well as type 2 diabetes (Methods Find. Exp. Clin. Pharmacol. 2005;27:547-54).

Another important constituent of mango (also found in olive, strawberry, fig, and various medicinal herbs) is the triterpene lupeol, which has been characterized as exhibiting potent antioxidant, antimutagenic, anti-inflammatory, and antiarthritic activity (Oncogene 2004;23:5203-14). A 2014 study by Sahu et al. also showed that M. indica leaves display some antityrosinase activity, though not as strongly as other medicinal plants, such as Emblica officinalis (Pak. J. Biol. Sci. 2014;17:146-50).

Anticancer, antioxidant, and antiphotoaging activity

In 2004, Saleem et al. demonstrated that topically applied lupeol exhibited anti–tumor-promoting effects in a CD-1 mouse skin tumorigenesis model. Pretreatment with the mango constituent time- and dose-dependently inhibited multiple 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-mediated increases in edema, hyperplasia, epidermal ornithine decarboxylase (ODC) activity, as well as protein expression of ODC, cyclooxygenase 2 (COX-2) and nitric oxide synthase. Pretreated animals also experienced significantly lower tumor incidence and tumor body burden as well as a significant delay in tumor latency period. The researchers concluded that lupeol exerts anti–skin tumor promoting effects on CD-1 mice (Oncogene 2004;23:5203-14).

Three years later, Núñez-Sellés et al. reported that a mango stem bark extract (Vimang) developed in Cuba exhibited antioxidant, analgesic, anti-inflammatory, and immunomodulating activity in basic, preclinical, and clinical studies (Pharmacol. Res. 2007;55:351-8).

A 2009 toxicological analysis of Vimang, which has been formulated into tablets, creams, capsules, syrup, vaginal oval, and suppositories for various applications, revealed via irritant tests conducted on rabbits that the topical formulation was not irritating to the skin, generally, with minimal irritancy noted after vaginal application. No adverse effects were reported (Drug Chem. Toxicol. 2009;32:53-8).

In 2012, Li et al. discovered norathyriol (1,3,6,7-tetrahydroxy-9H-xanthen-9-one), a plant-derived chemopreventive metabolite of mangiferin, found in mango, Hypericum elegans, and Tripterospermum lanceolatum. They found that norathyriol significantly inhibited solar UV-induced skin carcinogenesis in mouse models. In vitro investigations revealed that the compound suppressed cell growth in mouse skin epidermal JB6 P+ cells at the level of G2-M phase arrest. The investigators concluded that this newly identified substance appears to act as a safe chemopreventive agent against UV-induced skin cancer (Cancer Res. 2012;72:260-70).

A year later, Song et al. assessed the protective effects of orally administered mango extract against UVB-induced cutaneous aging in HR-1 hairless male mice. The animals were divided into control, UVB-treated vehicle, and UVB-treated mango extract groups. The researchers found that mango extract significantly suppressed the increase in epidermal thickness and hypertrophy indicative of UVB treatment, with mean length of wrinkles significantly lower in the mango group compared with the UVB-treated vehicle group. Treatment with mango extract also led to a significant increase in collagen bundles in animals treated with UVB. The authors concluded that mango extract displayed antiphotoaging properties in hairless mice exposed to UVB (Photodermatol. Photoimmunol. Photomed. 2013;29:84-9).

Further, a 2014 in vitro study revealed that extracts of Helicanthus elastica growing on M. indica exhibited antioxidant activity. H. elastica is a hemiparasite that often grows on mango trees in India and is known to be a rich source of phenolic substances (J. Tradit. Complement. Med. 2014;4:285-8).

Topical delivery

Mandawgade and Patravale developed a mango butter skin care formulation in 2008 that was used to test skin repair in rat excision and incision wound models. A healing response was noted in both animal models. The formulation also was found to be effective in achieving complete repair of worn and cracked skin on the feet of all human volunteers in the study. The investigators concluded that the mango butter preparation delivers superlative emolliency and warrants consideration as an excipient agent in cosmeceutical products (Indian J. Pharm. Sci. 2008;70:539-42).

It is worth noting that cases of “mango dermatitis” (allergic contact dermatitis to the sap or skin of M. indica), manifesting in urticaria and eczematous rashes, have been reported (Australas. J. Dermatol. 1996;37:59-60; Int. J. Dermatol. 2004;43:195-6).

In 2014, Leanpolchareanchai et al. developed a microemulsion system containing Thai mango seed kernel extract that displayed strong skin enhancement results in ex vivo skin permeation studies (penetrating skin layers up to 60-fold higher than controls) and physicochemical stability over 6 months (Drug Chem. Toxicol. 2009;32:53-8). Thai mango seed kernel extract had previously been shown to exhibit anti–methicillin-resistant Staphylococcus aureus and antityrosinase characteristics, as well as strong free radical scavenging, antioxidant, anti-inflammatory, and hepatoprotective activities.(Molecules 2014;19:17107-29).

Conclusion

Evidence on the cutaneous applications of mango is emerging, but does not have a significant track record. That said, this fruit has long been used in traditional medicine for a range of indications, including skin disorders. Much more research is necessary, however, to ascertain how beneficial this fruit and its extracts may be. At the very least, there are few reports of adverse events associated with topical application.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in the Design District in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote the textbook “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and a book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). She has contributed to the Cosmeceutical Critique column in Dermatology News since January 2001. Her latest book, “Cosmeceuticals and Cosmetic Ingredients,” was published in November 2014. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Evolus, Galderma, GlaxoSmithKline, Kythera, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Topix Pharmaceuticals, and Unilever.

Warfarin tablets

SAN FRANCISCO—Monitoring warfarin using a modified prothrombin time (PT) test can improve anticoagulation stability and long-term clinical outcomes, result of the Fiix trial suggest.

With Fiix-PT—a test that only measures the activity of coagulation factors II and X—the effect of warfarin fluctuated less than with standard PT.

Fiix-PT also proved superior in reducing long-term, recurrent thromboembolism (TE), and it did not increase bleeding, despite the fact that the test omits factor VII activity.

However, most of these effects occurred only after the 6-month mark.

Pall T. Onundarson, MD, of Landspitali University Hospital and University of Iceland School of Medicine in Reykjavik, presented these results at the 2014 ASH Annual Meeting (abstract 347).

Dr Onundarson is a co-inventor of the Fiix-PT test and has stock in Fiix Diagnostics, a startup company with the two inventors of the test as majority shareholders.

“Why would anyone still be interested in warfarin in 2014,” Dr Onundarson asked the audience at ASH. “Even if warfarin is very efficacious . . ., managing warfarin is trouble. The dose varies between patients, and the main problem is that we have a fluctuating or unstable effect—namely, a fluctuating INR—and this leads to frequent dose adjustments and frequent testing.”

Dr Onundarson said the common wisdom is that the effect of warfarin fluctuates due to food interactions and drug interactions. But he and his colleagues speculated that the fluctuation is partly caused by conventional PT.

They noted that experiments have suggested the anticoagulation effect of warfarin is mainly influenced by a reduction in FII and FX activity, and FVII may have relatively little effect. Due to the short half-life of FVII and its strong influence on the PT, monitoring warfarin using PT may confound dosing.

With that in mind, the Fiix-PT test was designed to measure only the activity of FII and FX. And the researchers conducted the Fiix trial to compare Fiix-PT and conventional PT.

Their study included 1148 patients—573 in the Fiix-PT arm and 575 in the PT arm. Overall, about 69% of patients had atrial fibrillation, and 21% had venous thromboembolism. The median monitoring time was 1.7 years per patient in both arms.

The researchers noted that most outcomes were not significantly different between the 2 arms in the first 6 months, but, after that point, things changed. So they examined outcomes after 6 months in a secondary analysis.

From day 1 to 180, there was no significant difference between the Fiix-PT arm and the PT arm in the number of dose changes per patient year (5.3 and 6.5, respectively, P=0.08). However, from day 181 to 720, there were significantly fewer dose changes in the Fiix-PT arm (4.1 and 5.0, respectively, P=0.01).

The researchers assessed the median time within target range (TTR) during 4 periods of the study, and, although results fluctuated, there were significant differences in favor of Fiix-PT.

The median TTR was 85% in the Fiix-PT arm and 81% in the PT arm for days 1 to 180 (P=0.013); 85% and 90%, respectively, for days 181 to 360 (P<0.0003); 80% and 81%, respectively, for days 361 to 540 (P=0.34); and 87% and 79%, respectively, for days 541 to 720 (P<0.005).

Overall, there was no significant difference in the rate of TE or major bleeding between the Fiix-PT and PT arms. However, when the researchers excluded the first 6 months of observation, they noted a significant difference in the rate of TE in favor of Fiix-PT.

In the primary analysis (encompassing days 1 to 720), the TE rate per patient year was 1.2% in the Fiix-PT arm and 2.3% in the PT arm (P=0.09 for superiority, P<0.001 for non-inferiority). The major bleeding rates were 2.2% and 2.5%, respectively (P=0.8 for superiority, P<0.001 for non-inferiority).

In the secondary analysis (from day 181 to 720), Fiix-PT led to a superior long-term reduction in TE compared to conventional PT—1.1% and 2.2%, respectively (P=0.03 for superiority). But there was no significant difference in the rates of major bleeding—1.5% and 2.3%, respectively (P=0.5 for superiority).

“Compared to high-quality PT-INR monitoring, Fiix-PT increased the stability of warfarin anticoagulation,” Dr Onundarson said in closing. “Fiix-PT was clinically at least non-inferior to the INR in the primary analysis, and Fiix-PT led to superior long-term reduction in TE in the secondary analysis. Fiix-PT did not increase major bleeding, despite lowering the long-term thromboembolic rate and despite not being affected by FVII in the test sample.”

“So my overall conclusion is that a fluctuating INR during warfarin treatment is partly a confounding side effect of the PT itself. The data suggests that, if the PT is replaced with a monitoring test that is not affected by FVII, warfarin may become more stable than was previously assumed.”

Warfarin tablets

SAN FRANCISCO—Monitoring warfarin using a modified prothrombin time (PT) test can improve anticoagulation stability and long-term clinical outcomes, result of the Fiix trial suggest.

With Fiix-PT—a test that only measures the activity of coagulation factors II and X—the effect of warfarin fluctuated less than with standard PT.

Fiix-PT also proved superior in reducing long-term, recurrent thromboembolism (TE), and it did not increase bleeding, despite the fact that the test omits factor VII activity.

However, most of these effects occurred only after the 6-month mark.

Pall T. Onundarson, MD, of Landspitali University Hospital and University of Iceland School of Medicine in Reykjavik, presented these results at the 2014 ASH Annual Meeting (abstract 347).

Dr Onundarson is a co-inventor of the Fiix-PT test and has stock in Fiix Diagnostics, a startup company with the two inventors of the test as majority shareholders.

“Why would anyone still be interested in warfarin in 2014,” Dr Onundarson asked the audience at ASH. “Even if warfarin is very efficacious . . ., managing warfarin is trouble. The dose varies between patients, and the main problem is that we have a fluctuating or unstable effect—namely, a fluctuating INR—and this leads to frequent dose adjustments and frequent testing.”

Dr Onundarson said the common wisdom is that the effect of warfarin fluctuates due to food interactions and drug interactions. But he and his colleagues speculated that the fluctuation is partly caused by conventional PT.

They noted that experiments have suggested the anticoagulation effect of warfarin is mainly influenced by a reduction in FII and FX activity, and FVII may have relatively little effect. Due to the short half-life of FVII and its strong influence on the PT, monitoring warfarin using PT may confound dosing.

With that in mind, the Fiix-PT test was designed to measure only the activity of FII and FX. And the researchers conducted the Fiix trial to compare Fiix-PT and conventional PT.

Their study included 1148 patients—573 in the Fiix-PT arm and 575 in the PT arm. Overall, about 69% of patients had atrial fibrillation, and 21% had venous thromboembolism. The median monitoring time was 1.7 years per patient in both arms.

The researchers noted that most outcomes were not significantly different between the 2 arms in the first 6 months, but, after that point, things changed. So they examined outcomes after 6 months in a secondary analysis.

From day 1 to 180, there was no significant difference between the Fiix-PT arm and the PT arm in the number of dose changes per patient year (5.3 and 6.5, respectively, P=0.08). However, from day 181 to 720, there were significantly fewer dose changes in the Fiix-PT arm (4.1 and 5.0, respectively, P=0.01).

The researchers assessed the median time within target range (TTR) during 4 periods of the study, and, although results fluctuated, there were significant differences in favor of Fiix-PT.

The median TTR was 85% in the Fiix-PT arm and 81% in the PT arm for days 1 to 180 (P=0.013); 85% and 90%, respectively, for days 181 to 360 (P<0.0003); 80% and 81%, respectively, for days 361 to 540 (P=0.34); and 87% and 79%, respectively, for days 541 to 720 (P<0.005).

Overall, there was no significant difference in the rate of TE or major bleeding between the Fiix-PT and PT arms. However, when the researchers excluded the first 6 months of observation, they noted a significant difference in the rate of TE in favor of Fiix-PT.

In the primary analysis (encompassing days 1 to 720), the TE rate per patient year was 1.2% in the Fiix-PT arm and 2.3% in the PT arm (P=0.09 for superiority, P<0.001 for non-inferiority). The major bleeding rates were 2.2% and 2.5%, respectively (P=0.8 for superiority, P<0.001 for non-inferiority).

In the secondary analysis (from day 181 to 720), Fiix-PT led to a superior long-term reduction in TE compared to conventional PT—1.1% and 2.2%, respectively (P=0.03 for superiority). But there was no significant difference in the rates of major bleeding—1.5% and 2.3%, respectively (P=0.5 for superiority).

“Compared to high-quality PT-INR monitoring, Fiix-PT increased the stability of warfarin anticoagulation,” Dr Onundarson said in closing. “Fiix-PT was clinically at least non-inferior to the INR in the primary analysis, and Fiix-PT led to superior long-term reduction in TE in the secondary analysis. Fiix-PT did not increase major bleeding, despite lowering the long-term thromboembolic rate and despite not being affected by FVII in the test sample.”

“So my overall conclusion is that a fluctuating INR during warfarin treatment is partly a confounding side effect of the PT itself. The data suggests that, if the PT is replaced with a monitoring test that is not affected by FVII, warfarin may become more stable than was previously assumed.”

Warfarin tablets

SAN FRANCISCO—Monitoring warfarin using a modified prothrombin time (PT) test can improve anticoagulation stability and long-term clinical outcomes, result of the Fiix trial suggest.

With Fiix-PT—a test that only measures the activity of coagulation factors II and X—the effect of warfarin fluctuated less than with standard PT.

Fiix-PT also proved superior in reducing long-term, recurrent thromboembolism (TE), and it did not increase bleeding, despite the fact that the test omits factor VII activity.

However, most of these effects occurred only after the 6-month mark.

Pall T. Onundarson, MD, of Landspitali University Hospital and University of Iceland School of Medicine in Reykjavik, presented these results at the 2014 ASH Annual Meeting (abstract 347).

Dr Onundarson is a co-inventor of the Fiix-PT test and has stock in Fiix Diagnostics, a startup company with the two inventors of the test as majority shareholders.

“Why would anyone still be interested in warfarin in 2014,” Dr Onundarson asked the audience at ASH. “Even if warfarin is very efficacious . . ., managing warfarin is trouble. The dose varies between patients, and the main problem is that we have a fluctuating or unstable effect—namely, a fluctuating INR—and this leads to frequent dose adjustments and frequent testing.”

Dr Onundarson said the common wisdom is that the effect of warfarin fluctuates due to food interactions and drug interactions. But he and his colleagues speculated that the fluctuation is partly caused by conventional PT.

They noted that experiments have suggested the anticoagulation effect of warfarin is mainly influenced by a reduction in FII and FX activity, and FVII may have relatively little effect. Due to the short half-life of FVII and its strong influence on the PT, monitoring warfarin using PT may confound dosing.

With that in mind, the Fiix-PT test was designed to measure only the activity of FII and FX. And the researchers conducted the Fiix trial to compare Fiix-PT and conventional PT.

Their study included 1148 patients—573 in the Fiix-PT arm and 575 in the PT arm. Overall, about 69% of patients had atrial fibrillation, and 21% had venous thromboembolism. The median monitoring time was 1.7 years per patient in both arms.

The researchers noted that most outcomes were not significantly different between the 2 arms in the first 6 months, but, after that point, things changed. So they examined outcomes after 6 months in a secondary analysis.

From day 1 to 180, there was no significant difference between the Fiix-PT arm and the PT arm in the number of dose changes per patient year (5.3 and 6.5, respectively, P=0.08). However, from day 181 to 720, there were significantly fewer dose changes in the Fiix-PT arm (4.1 and 5.0, respectively, P=0.01).

The researchers assessed the median time within target range (TTR) during 4 periods of the study, and, although results fluctuated, there were significant differences in favor of Fiix-PT.

The median TTR was 85% in the Fiix-PT arm and 81% in the PT arm for days 1 to 180 (P=0.013); 85% and 90%, respectively, for days 181 to 360 (P<0.0003); 80% and 81%, respectively, for days 361 to 540 (P=0.34); and 87% and 79%, respectively, for days 541 to 720 (P<0.005).

Overall, there was no significant difference in the rate of TE or major bleeding between the Fiix-PT and PT arms. However, when the researchers excluded the first 6 months of observation, they noted a significant difference in the rate of TE in favor of Fiix-PT.

In the primary analysis (encompassing days 1 to 720), the TE rate per patient year was 1.2% in the Fiix-PT arm and 2.3% in the PT arm (P=0.09 for superiority, P<0.001 for non-inferiority). The major bleeding rates were 2.2% and 2.5%, respectively (P=0.8 for superiority, P<0.001 for non-inferiority).

In the secondary analysis (from day 181 to 720), Fiix-PT led to a superior long-term reduction in TE compared to conventional PT—1.1% and 2.2%, respectively (P=0.03 for superiority). But there was no significant difference in the rates of major bleeding—1.5% and 2.3%, respectively (P=0.5 for superiority).

“Compared to high-quality PT-INR monitoring, Fiix-PT increased the stability of warfarin anticoagulation,” Dr Onundarson said in closing. “Fiix-PT was clinically at least non-inferior to the INR in the primary analysis, and Fiix-PT led to superior long-term reduction in TE in the secondary analysis. Fiix-PT did not increase major bleeding, despite lowering the long-term thromboembolic rate and despite not being affected by FVII in the test sample.”

“So my overall conclusion is that a fluctuating INR during warfarin treatment is partly a confounding side effect of the PT itself. The data suggests that, if the PT is replaced with a monitoring test that is not affected by FVII, warfarin may become more stable than was previously assumed.”

Prescription medications

Credit: Steven Harbour

The National Health Service (NHS) has increased the budget for England’s Cancer Drugs Fund (CDF) and  added a new drug to treat 2 hematologic malignancies, but 5 other blood cancer drugs will be removed from the fund in March.

The budget for the CDF will grow from £200 million in 2013/14 to £280 million in 2014/15.

However, 16 drugs (for 25 different indications) will no longer be offered through the fund as of March 12, 2015.

Still, the NHS said it has taken steps to ensure patients can receive appropriate treatment.

Review leads to cuts

A national panel of oncologists, pharmacists, and patient representatives independently reviewed the drug indications currently available through the CDF, plus new applications.

They evaluated the clinical benefit, survival, quality of life, toxicity, and safety associated with each treatment, as well as the level of unmet need and the median cost per patient. In cases where the high cost of a drug would lead to its exclusion from CDF, manufacturers were given an opportunity to reduce prices.

The result of the review is that 59 of the 84 most effective currently approved indications of drugs will rollover into the CDF next year, creating room for new drug indications that will be funded for the first time.

These are panitumumab for bowel cancer, ibrutinib for mantle cell lymphoma, and ibrutinib for chronic lymphocytic leukemia.

However, 16 drugs, including 5 blood cancer drugs—bendamustine, bortezomib, bosutinib, dasatinib, and ofatumumab—will no longer be offered through the CDF.

Following these changes, the NHS will put 4 measures in place to ensure patients can receive appropriate treatment. First, any patient currently receiving a drug through the CDF will continue to receive it, regardless of whether it remains in the CDF.

Second, drugs that are the only therapy for the cancer in question will remain available through the CDF. Third, if the CDF panel removes a drug for a particular indication, some patients may instead be able to receive it in another line of therapy or receive an alternative CDF-approved drug.

And finally, clinicians can apply for their patient to receive a drug not available through the CDF on an exceptional basis.

Cuts to blood cancer drugs

The full list of cuts to the CDF is available on the NHS website, but the following list includes all drugs for hematologic malignancies that will no longer be available. These drugs will still be available for other indications, however.

1. Bendamustine for the treatment of low-grade lymphoma that is refractory to rituximab alone or in combination.
2. Bortezomib for the treatment of:

   • relapsed/refractory mantle cell lymphoma after 1 or more prior chemotherapies or stem cell transplant
   • relapsed multiple myeloma patients with a previous partial response or complete response of 6 months or more with bortezomib
   • relapsed Waldenstrom’s macroglobulinemia patients who received previous treatment with alkylating agents and purine analogues.

3. Bosutinib for the treatment of:

   • blast crisis chronic myeloid leukemia (CML) that is refractory to nilotinib or dasatinib if dasatinib was accessed via a clinical trial or via its current approved CDF indication
   • blast crisis CML where there is treatment intolerance, specifically, significant intolerance to dasatinib (grade 3 or 4 adverse events) if dasatinib was accessed via its current approved CDF indication.

4. Dasatinib for the treatment of lymphoid, blast crisis CML that is refractory to, significantly intolerant of, or resistant to prior therapy including imatinib (grade 3 or 4 adverse events); also when used as the 2nd- or 3rd-line treatment.
5. Ofatumumab for the treatment of CML as the 2nd- or 3rd-line indication and if the patient is refractory to treatment with fludarabine in combination and/or alemtuzumab or if treatment with fludarabine in combination and/or alemtuzumab is contraindicated.

More about the CDF and the NHS

The CDF—set up in 2010 and currently due to run until March 2016—is money the government has set aside to pay for cancer drugs that haven’t been approved by the National Institute for Health and Care Excellence (NICE) and aren’t available within the NHS in England. Most cancer drugs are routinely funded outside of the CDF.

NHS England said it is working with cancer charities, the pharmaceutical industry, and NICE to create a sustainable model for the commissioning of chemotherapy. The agency has also updated its procedures for evaluating drugs in the CDF, in an effort to ensure sustainability.

In addition, NHS England has set up an appeals process by which pharmaceutical companies can challenge the decision-making process.

And a newly assembled national taskforce, headed by Harpal Kumar, chief executive of Cancer Research UK, is set to produce a refreshed, 5-year cancer plan for the NHS.

Prescription medications

Credit: Steven Harbour

The National Health Service (NHS) has increased the budget for England’s Cancer Drugs Fund (CDF) and  added a new drug to treat 2 hematologic malignancies, but 5 other blood cancer drugs will be removed from the fund in March.

The budget for the CDF will grow from £200 million in 2013/14 to £280 million in 2014/15.

However, 16 drugs (for 25 different indications) will no longer be offered through the fund as of March 12, 2015.

Still, the NHS said it has taken steps to ensure patients can receive appropriate treatment.

Review leads to cuts

A national panel of oncologists, pharmacists, and patient representatives independently reviewed the drug indications currently available through the CDF, plus new applications.

They evaluated the clinical benefit, survival, quality of life, toxicity, and safety associated with each treatment, as well as the level of unmet need and the median cost per patient. In cases where the high cost of a drug would lead to its exclusion from CDF, manufacturers were given an opportunity to reduce prices.

The result of the review is that 59 of the 84 most effective currently approved indications of drugs will rollover into the CDF next year, creating room for new drug indications that will be funded for the first time.

These are panitumumab for bowel cancer, ibrutinib for mantle cell lymphoma, and ibrutinib for chronic lymphocytic leukemia.

However, 16 drugs, including 5 blood cancer drugs—bendamustine, bortezomib, bosutinib, dasatinib, and ofatumumab—will no longer be offered through the CDF.

Following these changes, the NHS will put 4 measures in place to ensure patients can receive appropriate treatment. First, any patient currently receiving a drug through the CDF will continue to receive it, regardless of whether it remains in the CDF.

Second, drugs that are the only therapy for the cancer in question will remain available through the CDF. Third, if the CDF panel removes a drug for a particular indication, some patients may instead be able to receive it in another line of therapy or receive an alternative CDF-approved drug.

And finally, clinicians can apply for their patient to receive a drug not available through the CDF on an exceptional basis.

Cuts to blood cancer drugs

The full list of cuts to the CDF is available on the NHS website, but the following list includes all drugs for hematologic malignancies that will no longer be available. These drugs will still be available for other indications, however.

1. Bendamustine for the treatment of low-grade lymphoma that is refractory to rituximab alone or in combination.
2. Bortezomib for the treatment of:

   • relapsed/refractory mantle cell lymphoma after 1 or more prior chemotherapies or stem cell transplant
   • relapsed multiple myeloma patients with a previous partial response or complete response of 6 months or more with bortezomib
   • relapsed Waldenstrom’s macroglobulinemia patients who received previous treatment with alkylating agents and purine analogues.

3. Bosutinib for the treatment of:

   • blast crisis chronic myeloid leukemia (CML) that is refractory to nilotinib or dasatinib if dasatinib was accessed via a clinical trial or via its current approved CDF indication
   • blast crisis CML where there is treatment intolerance, specifically, significant intolerance to dasatinib (grade 3 or 4 adverse events) if dasatinib was accessed via its current approved CDF indication.

4. Dasatinib for the treatment of lymphoid, blast crisis CML that is refractory to, significantly intolerant of, or resistant to prior therapy including imatinib (grade 3 or 4 adverse events); also when used as the 2nd- or 3rd-line treatment.
5. Ofatumumab for the treatment of CML as the 2nd- or 3rd-line indication and if the patient is refractory to treatment with fludarabine in combination and/or alemtuzumab or if treatment with fludarabine in combination and/or alemtuzumab is contraindicated.

More about the CDF and the NHS

The CDF—set up in 2010 and currently due to run until March 2016—is money the government has set aside to pay for cancer drugs that haven’t been approved by the National Institute for Health and Care Excellence (NICE) and aren’t available within the NHS in England. Most cancer drugs are routinely funded outside of the CDF.

NHS England said it is working with cancer charities, the pharmaceutical industry, and NICE to create a sustainable model for the commissioning of chemotherapy. The agency has also updated its procedures for evaluating drugs in the CDF, in an effort to ensure sustainability.

In addition, NHS England has set up an appeals process by which pharmaceutical companies can challenge the decision-making process.

And a newly assembled national taskforce, headed by Harpal Kumar, chief executive of Cancer Research UK, is set to produce a refreshed, 5-year cancer plan for the NHS.

Prescription medications

Credit: Steven Harbour

The National Health Service (NHS) has increased the budget for England’s Cancer Drugs Fund (CDF) and  added a new drug to treat 2 hematologic malignancies, but 5 other blood cancer drugs will be removed from the fund in March.

The budget for the CDF will grow from £200 million in 2013/14 to £280 million in 2014/15.

However, 16 drugs (for 25 different indications) will no longer be offered through the fund as of March 12, 2015.

Still, the NHS said it has taken steps to ensure patients can receive appropriate treatment.

Review leads to cuts

A national panel of oncologists, pharmacists, and patient representatives independently reviewed the drug indications currently available through the CDF, plus new applications.

They evaluated the clinical benefit, survival, quality of life, toxicity, and safety associated with each treatment, as well as the level of unmet need and the median cost per patient. In cases where the high cost of a drug would lead to its exclusion from CDF, manufacturers were given an opportunity to reduce prices.

The result of the review is that 59 of the 84 most effective currently approved indications of drugs will rollover into the CDF next year, creating room for new drug indications that will be funded for the first time.

These are panitumumab for bowel cancer, ibrutinib for mantle cell lymphoma, and ibrutinib for chronic lymphocytic leukemia.

However, 16 drugs, including 5 blood cancer drugs—bendamustine, bortezomib, bosutinib, dasatinib, and ofatumumab—will no longer be offered through the CDF.

Following these changes, the NHS will put 4 measures in place to ensure patients can receive appropriate treatment. First, any patient currently receiving a drug through the CDF will continue to receive it, regardless of whether it remains in the CDF.

Second, drugs that are the only therapy for the cancer in question will remain available through the CDF. Third, if the CDF panel removes a drug for a particular indication, some patients may instead be able to receive it in another line of therapy or receive an alternative CDF-approved drug.

And finally, clinicians can apply for their patient to receive a drug not available through the CDF on an exceptional basis.

Cuts to blood cancer drugs

The full list of cuts to the CDF is available on the NHS website, but the following list includes all drugs for hematologic malignancies that will no longer be available. These drugs will still be available for other indications, however.

1. Bendamustine for the treatment of low-grade lymphoma that is refractory to rituximab alone or in combination.
2. Bortezomib for the treatment of:

   • relapsed/refractory mantle cell lymphoma after 1 or more prior chemotherapies or stem cell transplant
   • relapsed multiple myeloma patients with a previous partial response or complete response of 6 months or more with bortezomib
   • relapsed Waldenstrom’s macroglobulinemia patients who received previous treatment with alkylating agents and purine analogues.

3. Bosutinib for the treatment of:

   • blast crisis chronic myeloid leukemia (CML) that is refractory to nilotinib or dasatinib if dasatinib was accessed via a clinical trial or via its current approved CDF indication
   • blast crisis CML where there is treatment intolerance, specifically, significant intolerance to dasatinib (grade 3 or 4 adverse events) if dasatinib was accessed via its current approved CDF indication.

4. Dasatinib for the treatment of lymphoid, blast crisis CML that is refractory to, significantly intolerant of, or resistant to prior therapy including imatinib (grade 3 or 4 adverse events); also when used as the 2nd- or 3rd-line treatment.
5. Ofatumumab for the treatment of CML as the 2nd- or 3rd-line indication and if the patient is refractory to treatment with fludarabine in combination and/or alemtuzumab or if treatment with fludarabine in combination and/or alemtuzumab is contraindicated.

More about the CDF and the NHS

The CDF—set up in 2010 and currently due to run until March 2016—is money the government has set aside to pay for cancer drugs that haven’t been approved by the National Institute for Health and Care Excellence (NICE) and aren’t available within the NHS in England. Most cancer drugs are routinely funded outside of the CDF.

NHS England said it is working with cancer charities, the pharmaceutical industry, and NICE to create a sustainable model for the commissioning of chemotherapy. The agency has also updated its procedures for evaluating drugs in the CDF, in an effort to ensure sustainability.

In addition, NHS England has set up an appeals process by which pharmaceutical companies can challenge the decision-making process.

And a newly assembled national taskforce, headed by Harpal Kumar, chief executive of Cancer Research UK, is set to produce a refreshed, 5-year cancer plan for the NHS.

Acute myeloid leukemia

In a phase 2 trial, an investigational drug conferred a significant improvement in survival when used as salvage therapy in poor-risk patients with acute myeloid leukemia (AML).

On the other hand, the drug did not provide any significant improvements over control treatment (investigator’s choice) in the entire population of AML patients in first relapse.

The drug, CPX-351, is a fixed-ratio combination of cytarabine and daunorubicin inside a lipid vesicle.

Researchers reported these results with CPX-351 in Cancer. The study was funded by Celator Pharmaceuticals, the company developing CPX-351, and the Leukemia and Lymphoma Society.

“Patients with first-relapse AML have generally a poor prognosis, with a limited likelihood of response following salvage treatment,” said study author Jorge Cortes, MD, of the MD Anderson Cancer Center in Houston, Texas.

“This is particularly true for patients classified by the EPI [European Prognostic Index] as poor-risk upon entering the trial.”

For this trial, Dr Cortes and his colleagues evaluated 125 patients, ages 18 to 65, from 35 centers in the US, Canada, and Europe. Patients had AML in first relapse after an initial complete remission lasting a month or longer.

They were stratified per the EPI into favorable-, intermediate-, and poor-risk groups based on the duration of their first complete remission, cytogenetics, age, and transplant history. Most patients (68%) were in the poor-risk group.

Patients were randomized 2:1 to receive CPX-351 (100 units/m² on days 1, 3, and 5 by 90-minute infusion) or the investigators’ choice of first salvage chemotherapy. The control treatment was usually based on cytarabine and an anthracycline, often with one or more additional agents.

Patient characteristics were largely well-balanced between the treatment arms. However, the CPX-351 group had a younger median age (52 years vs 56 years), more patients with secondary AML (12.3% vs 6.8%), and a higher rate of prior transplant (27.2% vs 15.9%).

Response and survival

Response rates were higher in the CPX-351 arm than in the control arm. The rates of complete response were 37% and 31.8%, respectively. And the rates of complete response with incomplete count recovery were 12.3% and 9.1%, respectively.

However, there was no significant difference in event-free survival (EFS) or overall survival (OS) between the treatment arms.

The median EFS was 4 months in the CPX-351 arm and 1.4 months in the control arm (hazard ratio[HR]=0.66, P=0.08). And the median OS was 8.5 months and 6.3 months, respectively (HR=0.75, P=0.19).

In the poor-risk population, there was no significant improvement in EFS with CPX-351, but there was a significant improvement in OS.

The median EFS was 1.8 months in the CPX-351 arm and 1.2 months in the control arm (HR=0.63, P=0.08). And the median OS was 6.5 months and 4.2 months, respectively (HR=0.55, P=0.02).

Safety and early mortality

The early mortality rate was similar between the treatment arms at 30 days—7.4% in the CPX-351 arm and 4.5% in the control arm—and at 60 days—14.8% and 15.9%, respectively. However, at 90 days, deaths were more frequent in the control arm—21.4% and 37.9%.

Patients in the CPX-351 arm had slower neutrophil recovery than those in the control arm—42 days and 34 days, respectively. The same was true for platelet recovery—45 days and 35 days, respectively.

Delayed hematologic recovery was associated with more infection-related events, such as febrile neutropenia, bacteremia, pneumonia, sepsis, urinary tract infection, pyrexia, and cellulitis.

The researchers believe these results, along with the previously published results from a phase 2 trial of CPX-351 in patients newly diagnosed with AML, support the phase 3 study of CPX-351 as a first-line therapy in older patients with high-risk (secondary) AML.

“We were very pleased to see promising response rates in this difficult-to-treat population,” Dr Cortes said. “And we eagerly await results from Celator’s pivotal phase 3 study of CPX-351, which could fulfill a considerable unmet need in AML.”

Acute myeloid leukemia

In a phase 2 trial, an investigational drug conferred a significant improvement in survival when used as salvage therapy in poor-risk patients with acute myeloid leukemia (AML).

On the other hand, the drug did not provide any significant improvements over control treatment (investigator’s choice) in the entire population of AML patients in first relapse.

The drug, CPX-351, is a fixed-ratio combination of cytarabine and daunorubicin inside a lipid vesicle.

Researchers reported these results with CPX-351 in Cancer. The study was funded by Celator Pharmaceuticals, the company developing CPX-351, and the Leukemia and Lymphoma Society.

“Patients with first-relapse AML have generally a poor prognosis, with a limited likelihood of response following salvage treatment,” said study author Jorge Cortes, MD, of the MD Anderson Cancer Center in Houston, Texas.

“This is particularly true for patients classified by the EPI [European Prognostic Index] as poor-risk upon entering the trial.”

For this trial, Dr Cortes and his colleagues evaluated 125 patients, ages 18 to 65, from 35 centers in the US, Canada, and Europe. Patients had AML in first relapse after an initial complete remission lasting a month or longer.

They were stratified per the EPI into favorable-, intermediate-, and poor-risk groups based on the duration of their first complete remission, cytogenetics, age, and transplant history. Most patients (68%) were in the poor-risk group.

Patients were randomized 2:1 to receive CPX-351 (100 units/m² on days 1, 3, and 5 by 90-minute infusion) or the investigators’ choice of first salvage chemotherapy. The control treatment was usually based on cytarabine and an anthracycline, often with one or more additional agents.

Patient characteristics were largely well-balanced between the treatment arms. However, the CPX-351 group had a younger median age (52 years vs 56 years), more patients with secondary AML (12.3% vs 6.8%), and a higher rate of prior transplant (27.2% vs 15.9%).

Response and survival

Response rates were higher in the CPX-351 arm than in the control arm. The rates of complete response were 37% and 31.8%, respectively. And the rates of complete response with incomplete count recovery were 12.3% and 9.1%, respectively.

However, there was no significant difference in event-free survival (EFS) or overall survival (OS) between the treatment arms.

The median EFS was 4 months in the CPX-351 arm and 1.4 months in the control arm (hazard ratio[HR]=0.66, P=0.08). And the median OS was 8.5 months and 6.3 months, respectively (HR=0.75, P=0.19).

In the poor-risk population, there was no significant improvement in EFS with CPX-351, but there was a significant improvement in OS.

The median EFS was 1.8 months in the CPX-351 arm and 1.2 months in the control arm (HR=0.63, P=0.08). And the median OS was 6.5 months and 4.2 months, respectively (HR=0.55, P=0.02).

Safety and early mortality

The early mortality rate was similar between the treatment arms at 30 days—7.4% in the CPX-351 arm and 4.5% in the control arm—and at 60 days—14.8% and 15.9%, respectively. However, at 90 days, deaths were more frequent in the control arm—21.4% and 37.9%.

Patients in the CPX-351 arm had slower neutrophil recovery than those in the control arm—42 days and 34 days, respectively. The same was true for platelet recovery—45 days and 35 days, respectively.

Delayed hematologic recovery was associated with more infection-related events, such as febrile neutropenia, bacteremia, pneumonia, sepsis, urinary tract infection, pyrexia, and cellulitis.

The researchers believe these results, along with the previously published results from a phase 2 trial of CPX-351 in patients newly diagnosed with AML, support the phase 3 study of CPX-351 as a first-line therapy in older patients with high-risk (secondary) AML.

“We were very pleased to see promising response rates in this difficult-to-treat population,” Dr Cortes said. “And we eagerly await results from Celator’s pivotal phase 3 study of CPX-351, which could fulfill a considerable unmet need in AML.”

Acute myeloid leukemia

In a phase 2 trial, an investigational drug conferred a significant improvement in survival when used as salvage therapy in poor-risk patients with acute myeloid leukemia (AML).

On the other hand, the drug did not provide any significant improvements over control treatment (investigator’s choice) in the entire population of AML patients in first relapse.

The drug, CPX-351, is a fixed-ratio combination of cytarabine and daunorubicin inside a lipid vesicle.

Researchers reported these results with CPX-351 in Cancer. The study was funded by Celator Pharmaceuticals, the company developing CPX-351, and the Leukemia and Lymphoma Society.

“Patients with first-relapse AML have generally a poor prognosis, with a limited likelihood of response following salvage treatment,” said study author Jorge Cortes, MD, of the MD Anderson Cancer Center in Houston, Texas.

“This is particularly true for patients classified by the EPI [European Prognostic Index] as poor-risk upon entering the trial.”

For this trial, Dr Cortes and his colleagues evaluated 125 patients, ages 18 to 65, from 35 centers in the US, Canada, and Europe. Patients had AML in first relapse after an initial complete remission lasting a month or longer.

They were stratified per the EPI into favorable-, intermediate-, and poor-risk groups based on the duration of their first complete remission, cytogenetics, age, and transplant history. Most patients (68%) were in the poor-risk group.

Patients were randomized 2:1 to receive CPX-351 (100 units/m² on days 1, 3, and 5 by 90-minute infusion) or the investigators’ choice of first salvage chemotherapy. The control treatment was usually based on cytarabine and an anthracycline, often with one or more additional agents.

Patient characteristics were largely well-balanced between the treatment arms. However, the CPX-351 group had a younger median age (52 years vs 56 years), more patients with secondary AML (12.3% vs 6.8%), and a higher rate of prior transplant (27.2% vs 15.9%).

Response and survival

Response rates were higher in the CPX-351 arm than in the control arm. The rates of complete response were 37% and 31.8%, respectively. And the rates of complete response with incomplete count recovery were 12.3% and 9.1%, respectively.

However, there was no significant difference in event-free survival (EFS) or overall survival (OS) between the treatment arms.

The median EFS was 4 months in the CPX-351 arm and 1.4 months in the control arm (hazard ratio[HR]=0.66, P=0.08). And the median OS was 8.5 months and 6.3 months, respectively (HR=0.75, P=0.19).

In the poor-risk population, there was no significant improvement in EFS with CPX-351, but there was a significant improvement in OS.

The median EFS was 1.8 months in the CPX-351 arm and 1.2 months in the control arm (HR=0.63, P=0.08). And the median OS was 6.5 months and 4.2 months, respectively (HR=0.55, P=0.02).

Safety and early mortality

The early mortality rate was similar between the treatment arms at 30 days—7.4% in the CPX-351 arm and 4.5% in the control arm—and at 60 days—14.8% and 15.9%, respectively. However, at 90 days, deaths were more frequent in the control arm—21.4% and 37.9%.

Patients in the CPX-351 arm had slower neutrophil recovery than those in the control arm—42 days and 34 days, respectively. The same was true for platelet recovery—45 days and 35 days, respectively.

Delayed hematologic recovery was associated with more infection-related events, such as febrile neutropenia, bacteremia, pneumonia, sepsis, urinary tract infection, pyrexia, and cellulitis.

The researchers believe these results, along with the previously published results from a phase 2 trial of CPX-351 in patients newly diagnosed with AML, support the phase 3 study of CPX-351 as a first-line therapy in older patients with high-risk (secondary) AML.

“We were very pleased to see promising response rates in this difficult-to-treat population,” Dr Cortes said. “And we eagerly await results from Celator’s pivotal phase 3 study of CPX-351, which could fulfill a considerable unmet need in AML.”

A severe flu season will have hospitalists dealing with increased patient censuses and the struggle of keeping staffers healthy and available, according to two physicians.

The CDC recently announced that all but seven states are dealing with widespread flu activity. Two of the states not yet seriously affected, California and New York, are among the highest population centers, prodding many to speculate that the flu will worsen in those areas and the overall season will rank among the worst in recent memory.

As a result, hospitalists across the country should expect to see more patients admitted for flu, as well as potential boarding of sick patients as EDs deal with higher patient counts, according to Alice Pong, MD, an infectious disease specialist at Rady Children’s Hospital in San Diego.

"[Hospitalists] deal with the increased number of actually otherwise healthy people who get flu, who then are sick enough to need to be in the hospital," Dr. Pong says, "and they get the chronically ill people with underlying disease who get the flu and get sicker."

Dr. Pong suggests tips to deal with flu season:

• Have a surge plan in place to handle larger censuses. Similarly, have staffing plans to cover shifts when a doctor needs to stay home sick or take care of a sick family member;
• Redouble focus on hygiene. Hand washing is even more important to prevent the spread of infectious disease within hospitals; and
• Work with infectious disease professionals. Take their cues and seek them out with questions about flu prevention.

Team Hospitalist member James O'Callaghan, MD, FHM, says that having staff members or their families get sick can be a larger concern in smaller groups. Dr. O'Callaghan, a regional pediatric hospitalist at EvergreenHealth in Kirkland, Wash., and a medical hospitalist at Seattle Children's, says losing one staff member in a small hospitalist group can be troublesome.

"We're only a 4.0 [full-time equivalent] group, and there's only one of us working per day," he says. "I don't have anybody on standby that I can just, with the press of button, activate if somebody gets sick." TH

Visit our website for more information on infectious diseases.

A severe flu season will have hospitalists dealing with increased patient censuses and the struggle of keeping staffers healthy and available, according to two physicians.

The CDC recently announced that all but seven states are dealing with widespread flu activity. Two of the states not yet seriously affected, California and New York, are among the highest population centers, prodding many to speculate that the flu will worsen in those areas and the overall season will rank among the worst in recent memory.

As a result, hospitalists across the country should expect to see more patients admitted for flu, as well as potential boarding of sick patients as EDs deal with higher patient counts, according to Alice Pong, MD, an infectious disease specialist at Rady Children’s Hospital in San Diego.

"[Hospitalists] deal with the increased number of actually otherwise healthy people who get flu, who then are sick enough to need to be in the hospital," Dr. Pong says, "and they get the chronically ill people with underlying disease who get the flu and get sicker."

Dr. Pong suggests tips to deal with flu season:

• Have a surge plan in place to handle larger censuses. Similarly, have staffing plans to cover shifts when a doctor needs to stay home sick or take care of a sick family member;
• Redouble focus on hygiene. Hand washing is even more important to prevent the spread of infectious disease within hospitals; and
• Work with infectious disease professionals. Take their cues and seek them out with questions about flu prevention.

Team Hospitalist member James O'Callaghan, MD, FHM, says that having staff members or their families get sick can be a larger concern in smaller groups. Dr. O'Callaghan, a regional pediatric hospitalist at EvergreenHealth in Kirkland, Wash., and a medical hospitalist at Seattle Children's, says losing one staff member in a small hospitalist group can be troublesome.

"We're only a 4.0 [full-time equivalent] group, and there's only one of us working per day," he says. "I don't have anybody on standby that I can just, with the press of button, activate if somebody gets sick." TH

Visit our website for more information on infectious diseases.

A severe flu season will have hospitalists dealing with increased patient censuses and the struggle of keeping staffers healthy and available, according to two physicians.

The CDC recently announced that all but seven states are dealing with widespread flu activity. Two of the states not yet seriously affected, California and New York, are among the highest population centers, prodding many to speculate that the flu will worsen in those areas and the overall season will rank among the worst in recent memory.

As a result, hospitalists across the country should expect to see more patients admitted for flu, as well as potential boarding of sick patients as EDs deal with higher patient counts, according to Alice Pong, MD, an infectious disease specialist at Rady Children’s Hospital in San Diego.

"[Hospitalists] deal with the increased number of actually otherwise healthy people who get flu, who then are sick enough to need to be in the hospital," Dr. Pong says, "and they get the chronically ill people with underlying disease who get the flu and get sicker."

Dr. Pong suggests tips to deal with flu season:

• Have a surge plan in place to handle larger censuses. Similarly, have staffing plans to cover shifts when a doctor needs to stay home sick or take care of a sick family member;
• Redouble focus on hygiene. Hand washing is even more important to prevent the spread of infectious disease within hospitals; and
• Work with infectious disease professionals. Take their cues and seek them out with questions about flu prevention.

Team Hospitalist member James O'Callaghan, MD, FHM, says that having staff members or their families get sick can be a larger concern in smaller groups. Dr. O'Callaghan, a regional pediatric hospitalist at EvergreenHealth in Kirkland, Wash., and a medical hospitalist at Seattle Children's, says losing one staff member in a small hospitalist group can be troublesome.

"We're only a 4.0 [full-time equivalent] group, and there's only one of us working per day," he says. "I don't have anybody on standby that I can just, with the press of button, activate if somebody gets sick." TH

Visit our website for more information on infectious diseases.

Hospitalists caring for patients with chronic liver disease should consider administering the hepatitis A vaccine upon discharge, says an expert from the CDC.

The recommendation is based on a new study published in Hepatology that shows the rate of hospitalizations caused by a hepatitis A virus (HAV) infection declined significantly in the U.S. from 2002 to 2011. It also reports that older patients and those with chronic liver disease are most likely to be hospitalized with HAV, says Melissa Collier, MD, MPH, a medical epidemiologist within the CDC's division of viral hepatitis.

Dr. Collier and colleagues analyzed ICD-9 codes from the National Inpatient Survey discharge data, focusing on U.S. residents hospitalized with a principal hepatitis A diagnosis and accompanying secondary diagnoses. They found that from 2002 to 2011:

• Rates of hospitalization for hepatitis A as a principal diagnosis decreased from 0.72/100,000 to 0.29/100,000 (P

• Mean age of those hospitalized increased from 37.6 years to 45.5 years (P

• Percentage of hepatitis A hospitalizations covered by Medicare increased from 12.4% to 22.7% (P

• Secondary, comorbid discharge diagnoses, including liver disease, hypertension, ischemic heart disease, disorders of lipid metabolism, and chronic liver disease, increased; and
• No changes were reported in patients’ length of stay or in-hospital deaths from hepatitis A, but persons with liver disease were hospitalized longer.

According to Dr. Collier, the drop in hospitalization rates could be explained by lower incidence of hepatitis A since the Advisory Committee on Immunization Practices (ACIP) recommended universal childhood vaccination in 2006.

Dr. Collier, who is a member of the ACIP hepatitis A working group, also points out that the ACIP recommends all patients with chronic liver disease be vaccinated. She says hospitalists should give patients with chronic liver disease the first dose of the vaccine upon discharge and ask those patients' PCPs to administer the second dose.

"Patients don't think about needing to be vaccinated, and if their physicians aren't recommending it, they aren't going to seek it," she says. Dr. Collier noted that data show only about 12% of people age 19 to 49 have received the hepatitis A vaccine. TH

Visit our website for more information on treating liver disease.

Hospitalists caring for patients with chronic liver disease should consider administering the hepatitis A vaccine upon discharge, says an expert from the CDC.

The recommendation is based on a new study published in Hepatology that shows the rate of hospitalizations caused by a hepatitis A virus (HAV) infection declined significantly in the U.S. from 2002 to 2011. It also reports that older patients and those with chronic liver disease are most likely to be hospitalized with HAV, says Melissa Collier, MD, MPH, a medical epidemiologist within the CDC's division of viral hepatitis.

Dr. Collier and colleagues analyzed ICD-9 codes from the National Inpatient Survey discharge data, focusing on U.S. residents hospitalized with a principal hepatitis A diagnosis and accompanying secondary diagnoses. They found that from 2002 to 2011:

• Rates of hospitalization for hepatitis A as a principal diagnosis decreased from 0.72/100,000 to 0.29/100,000 (P

• Mean age of those hospitalized increased from 37.6 years to 45.5 years (P

• Percentage of hepatitis A hospitalizations covered by Medicare increased from 12.4% to 22.7% (P

• Secondary, comorbid discharge diagnoses, including liver disease, hypertension, ischemic heart disease, disorders of lipid metabolism, and chronic liver disease, increased; and
• No changes were reported in patients’ length of stay or in-hospital deaths from hepatitis A, but persons with liver disease were hospitalized longer.

According to Dr. Collier, the drop in hospitalization rates could be explained by lower incidence of hepatitis A since the Advisory Committee on Immunization Practices (ACIP) recommended universal childhood vaccination in 2006.

Dr. Collier, who is a member of the ACIP hepatitis A working group, also points out that the ACIP recommends all patients with chronic liver disease be vaccinated. She says hospitalists should give patients with chronic liver disease the first dose of the vaccine upon discharge and ask those patients' PCPs to administer the second dose.

"Patients don't think about needing to be vaccinated, and if their physicians aren't recommending it, they aren't going to seek it," she says. Dr. Collier noted that data show only about 12% of people age 19 to 49 have received the hepatitis A vaccine. TH

Visit our website for more information on treating liver disease.

Hospitalists caring for patients with chronic liver disease should consider administering the hepatitis A vaccine upon discharge, says an expert from the CDC.

The recommendation is based on a new study published in Hepatology that shows the rate of hospitalizations caused by a hepatitis A virus (HAV) infection declined significantly in the U.S. from 2002 to 2011. It also reports that older patients and those with chronic liver disease are most likely to be hospitalized with HAV, says Melissa Collier, MD, MPH, a medical epidemiologist within the CDC's division of viral hepatitis.

Dr. Collier and colleagues analyzed ICD-9 codes from the National Inpatient Survey discharge data, focusing on U.S. residents hospitalized with a principal hepatitis A diagnosis and accompanying secondary diagnoses. They found that from 2002 to 2011:

• Rates of hospitalization for hepatitis A as a principal diagnosis decreased from 0.72/100,000 to 0.29/100,000 (P

• Mean age of those hospitalized increased from 37.6 years to 45.5 years (P

• Percentage of hepatitis A hospitalizations covered by Medicare increased from 12.4% to 22.7% (P

• Secondary, comorbid discharge diagnoses, including liver disease, hypertension, ischemic heart disease, disorders of lipid metabolism, and chronic liver disease, increased; and
• No changes were reported in patients’ length of stay or in-hospital deaths from hepatitis A, but persons with liver disease were hospitalized longer.

According to Dr. Collier, the drop in hospitalization rates could be explained by lower incidence of hepatitis A since the Advisory Committee on Immunization Practices (ACIP) recommended universal childhood vaccination in 2006.

Dr. Collier, who is a member of the ACIP hepatitis A working group, also points out that the ACIP recommends all patients with chronic liver disease be vaccinated. She says hospitalists should give patients with chronic liver disease the first dose of the vaccine upon discharge and ask those patients' PCPs to administer the second dose.

"Patients don't think about needing to be vaccinated, and if their physicians aren't recommending it, they aren't going to seek it," she says. Dr. Collier noted that data show only about 12% of people age 19 to 49 have received the hepatitis A vaccine. TH

Visit our website for more information on treating liver disease.

Microneedling, or skin needling, is an aesthetic technique used for decades prior to resurfacing lasers, but it has recently experienced a surge in popularity, particularly for ethnic skin. In 1995, subcision or dermal needling was identified as an effective treatment for scars. Since then, the technique initially referred to as collagen induction therapy has become a staple in the treatment of acne scars, surgical scars, photo aging, and stretch marks.

The skin needling technique involves using fine sterile needles 0.1mm-2.5 mm in length that repeatedly pierce the stratum corneum, producing microscopic “holes” in the dermis. These microscopic wounds lead to the release of growth factors stimulating the formation of new collagen, elastin, and neovascularization in the dermis. There are many brands and manufacturers of microneedling tools on the market, including dermarollers, Dermapen, Dermastamp, Cosmopen, and multiple other in-office and at-home devices. At-home devices usually have shorter needles and provide significantly less penetration and injury, and therefore may be less effective.

Prior to the procedure, patients are often anesthetized with topical anesthesia without vasoconstrictors for 1 hour. The area is cleaned with sterile gauze and alcohol or Hibiclens, and a microneedling device is used to either roll or prick the skin in multiple alternating passes. The depth of penetration, number of passes, and degree of overlap is highly dependent on the underlying condition, the area being treated, the brand of device used, and the length and frequency of the needle insertion. Petechiae and pinpoint bleeding occur during the treatment. Treatments are usually done 4-6 weeks apart. Post procedure, the patient often experiences mild erythema, bruising, and some mild edema.

This technique has been particularly beneficial to patients with skin of color who are not candidates for factional lasers because of the risks of hyperpigmentation and scarring. There is low risk of hyper- or hypopigmentation with microneedling, and multiple treatments can be performed in patients with types III-VI skin and those with a history of melasma.

Contraindications and precautions when considering microneedling include: history of keloid or hypertrophic scarring,recent skin rashes, history of herpes simplex infections if the perioral area is being treated, and the presence of raised moles, warts, or any raised lesions on the targeted area. Absolute contraindications include: scleroderma, collagen vascular diseases clotting problems, active bacterial or fungal infection, and immunosuppression.

Microneedling is a safe, effective, in-office procedure with a range of uses. Many new indications are currently being explored. In my practice, we have used microneedling for atrophic scars, repigmentation of depigmented scars and vitiligo, stimulation of hair regrowth in noninflammatory alopecias, and treatment of burn scars. Patients are generally very happy with the quick treatment time, minimal downtime, and overall long-term results.

References

1. Orentreich DS, Orentreich N. Subcutaneous incisionless (subcision) surgery for the correction of depressed scars and wrinkles. Dermatol. Surg. 1995;21:6543-9.

2. Camirand A, Doucet J. Needle dermabrasion. Aesthetic Plast. Surg. 1997;21:48-51.

3. Fernandes D. Minimally invasive percutaneous collagen induction. Oral Maxillofac. Surg. Clin. North Am. 2006;17:51-63.

4. Aust MC, Fernandes D, Kolokythas P, Kaplan HM, Vogt PM. Percutaneous collagen induction therapy: An alternative treatment for scars, wrinkles and skin laxity. Plast. Reconstr. Surg. 2008;21:1421-9.

5. Fernandes D, Signorini M. Combating photoaging with percutaneous collagen induction. Clin. Dermatol. 2008;26:192-9.

6. Aust MC, Reimers K, Repenning C, Stahl F, Jahn S, Guggenheim M et al. Percutaneous collagen induction: Minimally invasive skin rejuvenation without risk of hyperpigmentation – fact or fiction? Plast. Reconstr. Surg. 2008;122:1553-63.

7. Fabbrocini G, De Vita V, Pastore F, et al. Collagen induction therapy for the treatment of upper lip wrinkles. J. Dermatolog. Treat. 2012;23:144-52. 8. Majid I. Microneedling therapy in atrophic facial scars: an objective assessment. J. Cutan. Aesthet. Surg. 2009;2:26-30.

9. Doddaballapur S. Microneedling with dermaroller. J. Cutan. Aesthet. Surg 2009;2: 110-11.

10. Dogra S, Yadav S. Sarangal R. Microneedling for acne scars in Asian skin type: an effective low cost treatment modality. J. Cosmet. Dermatol. 2014;13:180-7.

Dr. Talakoub and Dr. Wesley are cocontributors to a monthly Aesthetic Dermatology column in Dermatology News. Dr. Talakoub is in private practice in McLean, Va. Dr. Wesley practices dermatology in Beverly Hills, Calif. This month’s column is by Dr. Talakoub.

Microneedling, or skin needling, is an aesthetic technique used for decades prior to resurfacing lasers, but it has recently experienced a surge in popularity, particularly for ethnic skin. In 1995, subcision or dermal needling was identified as an effective treatment for scars. Since then, the technique initially referred to as collagen induction therapy has become a staple in the treatment of acne scars, surgical scars, photo aging, and stretch marks.

The skin needling technique involves using fine sterile needles 0.1mm-2.5 mm in length that repeatedly pierce the stratum corneum, producing microscopic “holes” in the dermis. These microscopic wounds lead to the release of growth factors stimulating the formation of new collagen, elastin, and neovascularization in the dermis. There are many brands and manufacturers of microneedling tools on the market, including dermarollers, Dermapen, Dermastamp, Cosmopen, and multiple other in-office and at-home devices. At-home devices usually have shorter needles and provide significantly less penetration and injury, and therefore may be less effective.

Prior to the procedure, patients are often anesthetized with topical anesthesia without vasoconstrictors for 1 hour. The area is cleaned with sterile gauze and alcohol or Hibiclens, and a microneedling device is used to either roll or prick the skin in multiple alternating passes. The depth of penetration, number of passes, and degree of overlap is highly dependent on the underlying condition, the area being treated, the brand of device used, and the length and frequency of the needle insertion. Petechiae and pinpoint bleeding occur during the treatment. Treatments are usually done 4-6 weeks apart. Post procedure, the patient often experiences mild erythema, bruising, and some mild edema.

This technique has been particularly beneficial to patients with skin of color who are not candidates for factional lasers because of the risks of hyperpigmentation and scarring. There is low risk of hyper- or hypopigmentation with microneedling, and multiple treatments can be performed in patients with types III-VI skin and those with a history of melasma.

Contraindications and precautions when considering microneedling include: history of keloid or hypertrophic scarring,recent skin rashes, history of herpes simplex infections if the perioral area is being treated, and the presence of raised moles, warts, or any raised lesions on the targeted area. Absolute contraindications include: scleroderma, collagen vascular diseases clotting problems, active bacterial or fungal infection, and immunosuppression.

Microneedling is a safe, effective, in-office procedure with a range of uses. Many new indications are currently being explored. In my practice, we have used microneedling for atrophic scars, repigmentation of depigmented scars and vitiligo, stimulation of hair regrowth in noninflammatory alopecias, and treatment of burn scars. Patients are generally very happy with the quick treatment time, minimal downtime, and overall long-term results.

References

1. Orentreich DS, Orentreich N. Subcutaneous incisionless (subcision) surgery for the correction of depressed scars and wrinkles. Dermatol. Surg. 1995;21:6543-9.

2. Camirand A, Doucet J. Needle dermabrasion. Aesthetic Plast. Surg. 1997;21:48-51.

3. Fernandes D. Minimally invasive percutaneous collagen induction. Oral Maxillofac. Surg. Clin. North Am. 2006;17:51-63.

4. Aust MC, Fernandes D, Kolokythas P, Kaplan HM, Vogt PM. Percutaneous collagen induction therapy: An alternative treatment for scars, wrinkles and skin laxity. Plast. Reconstr. Surg. 2008;21:1421-9.

5. Fernandes D, Signorini M. Combating photoaging with percutaneous collagen induction. Clin. Dermatol. 2008;26:192-9.

6. Aust MC, Reimers K, Repenning C, Stahl F, Jahn S, Guggenheim M et al. Percutaneous collagen induction: Minimally invasive skin rejuvenation without risk of hyperpigmentation – fact or fiction? Plast. Reconstr. Surg. 2008;122:1553-63.

7. Fabbrocini G, De Vita V, Pastore F, et al. Collagen induction therapy for the treatment of upper lip wrinkles. J. Dermatolog. Treat. 2012;23:144-52. 8. Majid I. Microneedling therapy in atrophic facial scars: an objective assessment. J. Cutan. Aesthet. Surg. 2009;2:26-30.

9. Doddaballapur S. Microneedling with dermaroller. J. Cutan. Aesthet. Surg 2009;2: 110-11.

10. Dogra S, Yadav S. Sarangal R. Microneedling for acne scars in Asian skin type: an effective low cost treatment modality. J. Cosmet. Dermatol. 2014;13:180-7.

Dr. Talakoub and Dr. Wesley are cocontributors to a monthly Aesthetic Dermatology column in Dermatology News. Dr. Talakoub is in private practice in McLean, Va. Dr. Wesley practices dermatology in Beverly Hills, Calif. This month’s column is by Dr. Talakoub.

Microneedling, or skin needling, is an aesthetic technique used for decades prior to resurfacing lasers, but it has recently experienced a surge in popularity, particularly for ethnic skin. In 1995, subcision or dermal needling was identified as an effective treatment for scars. Since then, the technique initially referred to as collagen induction therapy has become a staple in the treatment of acne scars, surgical scars, photo aging, and stretch marks.

The skin needling technique involves using fine sterile needles 0.1mm-2.5 mm in length that repeatedly pierce the stratum corneum, producing microscopic “holes” in the dermis. These microscopic wounds lead to the release of growth factors stimulating the formation of new collagen, elastin, and neovascularization in the dermis. There are many brands and manufacturers of microneedling tools on the market, including dermarollers, Dermapen, Dermastamp, Cosmopen, and multiple other in-office and at-home devices. At-home devices usually have shorter needles and provide significantly less penetration and injury, and therefore may be less effective.

Prior to the procedure, patients are often anesthetized with topical anesthesia without vasoconstrictors for 1 hour. The area is cleaned with sterile gauze and alcohol or Hibiclens, and a microneedling device is used to either roll or prick the skin in multiple alternating passes. The depth of penetration, number of passes, and degree of overlap is highly dependent on the underlying condition, the area being treated, the brand of device used, and the length and frequency of the needle insertion. Petechiae and pinpoint bleeding occur during the treatment. Treatments are usually done 4-6 weeks apart. Post procedure, the patient often experiences mild erythema, bruising, and some mild edema.

This technique has been particularly beneficial to patients with skin of color who are not candidates for factional lasers because of the risks of hyperpigmentation and scarring. There is low risk of hyper- or hypopigmentation with microneedling, and multiple treatments can be performed in patients with types III-VI skin and those with a history of melasma.

Contraindications and precautions when considering microneedling include: history of keloid or hypertrophic scarring,recent skin rashes, history of herpes simplex infections if the perioral area is being treated, and the presence of raised moles, warts, or any raised lesions on the targeted area. Absolute contraindications include: scleroderma, collagen vascular diseases clotting problems, active bacterial or fungal infection, and immunosuppression.

Microneedling is a safe, effective, in-office procedure with a range of uses. Many new indications are currently being explored. In my practice, we have used microneedling for atrophic scars, repigmentation of depigmented scars and vitiligo, stimulation of hair regrowth in noninflammatory alopecias, and treatment of burn scars. Patients are generally very happy with the quick treatment time, minimal downtime, and overall long-term results.

References

1. Orentreich DS, Orentreich N. Subcutaneous incisionless (subcision) surgery for the correction of depressed scars and wrinkles. Dermatol. Surg. 1995;21:6543-9.

2. Camirand A, Doucet J. Needle dermabrasion. Aesthetic Plast. Surg. 1997;21:48-51.

3. Fernandes D. Minimally invasive percutaneous collagen induction. Oral Maxillofac. Surg. Clin. North Am. 2006;17:51-63.

4. Aust MC, Fernandes D, Kolokythas P, Kaplan HM, Vogt PM. Percutaneous collagen induction therapy: An alternative treatment for scars, wrinkles and skin laxity. Plast. Reconstr. Surg. 2008;21:1421-9.

5. Fernandes D, Signorini M. Combating photoaging with percutaneous collagen induction. Clin. Dermatol. 2008;26:192-9.

6. Aust MC, Reimers K, Repenning C, Stahl F, Jahn S, Guggenheim M et al. Percutaneous collagen induction: Minimally invasive skin rejuvenation without risk of hyperpigmentation – fact or fiction? Plast. Reconstr. Surg. 2008;122:1553-63.

7. Fabbrocini G, De Vita V, Pastore F, et al. Collagen induction therapy for the treatment of upper lip wrinkles. J. Dermatolog. Treat. 2012;23:144-52. 8. Majid I. Microneedling therapy in atrophic facial scars: an objective assessment. J. Cutan. Aesthet. Surg. 2009;2:26-30.

9. Doddaballapur S. Microneedling with dermaroller. J. Cutan. Aesthet. Surg 2009;2: 110-11.

10. Dogra S, Yadav S. Sarangal R. Microneedling for acne scars in Asian skin type: an effective low cost treatment modality. J. Cosmet. Dermatol. 2014;13:180-7.

Dr. Talakoub and Dr. Wesley are cocontributors to a monthly Aesthetic Dermatology column in Dermatology News. Dr. Talakoub is in private practice in McLean, Va. Dr. Wesley practices dermatology in Beverly Hills, Calif. This month’s column is by Dr. Talakoub.

The ongoing sea change in medicine has led to a substantial erosion of physician autonomy, and to ever-increasing administrative burdens that hit small practices the hardest. Does this mean that the independent private physician practice model is doomed, as some predict? Absolutely not; but it will force many solo practitioners and small groups to join forces to protect themselves.

Those practices that offer unique services, or fill an unmet niche, may be able to remain small; but most smaller practices will need to consider a larger alternative. In a previous column, I outlined the basics of one such protective strategy – merging two or more small practices into a larger entity – but there are other options to consider.

One attractive and relatively straightforward strategy is the formation of a cooperative group. In most areas, there are very likely several small practices in similar predicaments that might be receptive to discussing a collaboration on billing and purchasing. This allows each participant to maintain independence as a private practice, while pooling resources to ease the administrative burdens of all. Once that arrangement is in place, the group can consider more ambitious projects, such as the joint purchase of an EHR system, sharing of personnel to lower staffing costs, and an integrated scheduling system. The latter will be particularly attractive to participants in later stages of their careers who are considering an intermediate option, somewhere between full-time work and complete retirement.

After a time, when the structure is stabilized and everyone agrees that his or her individual and shared interests and goals are being met, an outright merger can be contemplated. Projects of this scope require careful planning and implementation, and should not be undertaken without the help of competent legal counsel and an experienced business consultant.

A more complex but increasingly popular option is to join other small practices and providers in an independent practice association (IPA). An IPA is a legal entity organized and directed by physicians for the purpose of negotiating contracts with insurance companies on their behalf. Because of its structure, an IPA is better positioned to enter into such financial arrangements, and to counterbalance the leverage of insurers, but there are legal issues to consider. Many IPAs are vulnerable to antitrust charges because they include competing health care providers. You should check with legal counsel before signing on to an IPA, to make sure that it abides by antitrust and price fixing laws. IPAs have also been known to fail, particularly in states where they are not adequately regulated.

A possible successor to IPAs is the accountable care organization (ACO), an entity born as a component of the Affordable Care Act. While the official definition remains nebulous, an ACO is basically a network of doctors and hospitals that shares financial and medical responsibility for providing coordinated and efficient care to patients. The goal of ACO participants is to limit unnecessary spending, both individually and collectively, according to criteria established by the Centers for Medicare & Medicaid Services, without compromising quality of care in the process. More than 600 ACOs had been approved by the CMS as of the beginning of 2014.

It is important to remember that the ACO model remains very much a work in progress. ACOs make providers jointly accountable for the health of their patients. They offer financial incentives to cooperate, and to save money by avoiding unnecessary tests and procedures. A key component is the sharing of information. Providers who save money while also meeting quality targets are theoretically entitled to a portion of the savings.

As with IPAs, ACO ventures involve a measure of risk. ACOs that fail to meet the CMS performance and savings benchmarks can be stuck with the bill for investments made to improve care, such as equipment and computer purchases and the hiring of mid-level providers and managers, and they may be assessed monetary penalties as well. ACOs sponsored by physicians or rural providers, however, can apply to receive payments in advance to help finance infrastructure investments – a concession the Obama administration made after receiving complaints from rural hospitals.

Clearly, the price of remaining autonomous will be significant, and many private practitioners will be unwilling to pay it: Only 36% of physicians remained in independent practice at the end of the 2013, according to data from the American Medical Association – down from 57% in 2000 – but those of us who remain committed to independence will find ways to preserve it. In medicine, as in life, those most responsive to change will survive and flourish.

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News.

The ongoing sea change in medicine has led to a substantial erosion of physician autonomy, and to ever-increasing administrative burdens that hit small practices the hardest. Does this mean that the independent private physician practice model is doomed, as some predict? Absolutely not; but it will force many solo practitioners and small groups to join forces to protect themselves.

Those practices that offer unique services, or fill an unmet niche, may be able to remain small; but most smaller practices will need to consider a larger alternative. In a previous column, I outlined the basics of one such protective strategy – merging two or more small practices into a larger entity – but there are other options to consider.

One attractive and relatively straightforward strategy is the formation of a cooperative group. In most areas, there are very likely several small practices in similar predicaments that might be receptive to discussing a collaboration on billing and purchasing. This allows each participant to maintain independence as a private practice, while pooling resources to ease the administrative burdens of all. Once that arrangement is in place, the group can consider more ambitious projects, such as the joint purchase of an EHR system, sharing of personnel to lower staffing costs, and an integrated scheduling system. The latter will be particularly attractive to participants in later stages of their careers who are considering an intermediate option, somewhere between full-time work and complete retirement.

After a time, when the structure is stabilized and everyone agrees that his or her individual and shared interests and goals are being met, an outright merger can be contemplated. Projects of this scope require careful planning and implementation, and should not be undertaken without the help of competent legal counsel and an experienced business consultant.

A more complex but increasingly popular option is to join other small practices and providers in an independent practice association (IPA). An IPA is a legal entity organized and directed by physicians for the purpose of negotiating contracts with insurance companies on their behalf. Because of its structure, an IPA is better positioned to enter into such financial arrangements, and to counterbalance the leverage of insurers, but there are legal issues to consider. Many IPAs are vulnerable to antitrust charges because they include competing health care providers. You should check with legal counsel before signing on to an IPA, to make sure that it abides by antitrust and price fixing laws. IPAs have also been known to fail, particularly in states where they are not adequately regulated.

A possible successor to IPAs is the accountable care organization (ACO), an entity born as a component of the Affordable Care Act. While the official definition remains nebulous, an ACO is basically a network of doctors and hospitals that shares financial and medical responsibility for providing coordinated and efficient care to patients. The goal of ACO participants is to limit unnecessary spending, both individually and collectively, according to criteria established by the Centers for Medicare & Medicaid Services, without compromising quality of care in the process. More than 600 ACOs had been approved by the CMS as of the beginning of 2014.

It is important to remember that the ACO model remains very much a work in progress. ACOs make providers jointly accountable for the health of their patients. They offer financial incentives to cooperate, and to save money by avoiding unnecessary tests and procedures. A key component is the sharing of information. Providers who save money while also meeting quality targets are theoretically entitled to a portion of the savings.

As with IPAs, ACO ventures involve a measure of risk. ACOs that fail to meet the CMS performance and savings benchmarks can be stuck with the bill for investments made to improve care, such as equipment and computer purchases and the hiring of mid-level providers and managers, and they may be assessed monetary penalties as well. ACOs sponsored by physicians or rural providers, however, can apply to receive payments in advance to help finance infrastructure investments – a concession the Obama administration made after receiving complaints from rural hospitals.

Clearly, the price of remaining autonomous will be significant, and many private practitioners will be unwilling to pay it: Only 36% of physicians remained in independent practice at the end of the 2013, according to data from the American Medical Association – down from 57% in 2000 – but those of us who remain committed to independence will find ways to preserve it. In medicine, as in life, those most responsive to change will survive and flourish.

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News.

The ongoing sea change in medicine has led to a substantial erosion of physician autonomy, and to ever-increasing administrative burdens that hit small practices the hardest. Does this mean that the independent private physician practice model is doomed, as some predict? Absolutely not; but it will force many solo practitioners and small groups to join forces to protect themselves.

Those practices that offer unique services, or fill an unmet niche, may be able to remain small; but most smaller practices will need to consider a larger alternative. In a previous column, I outlined the basics of one such protective strategy – merging two or more small practices into a larger entity – but there are other options to consider.

One attractive and relatively straightforward strategy is the formation of a cooperative group. In most areas, there are very likely several small practices in similar predicaments that might be receptive to discussing a collaboration on billing and purchasing. This allows each participant to maintain independence as a private practice, while pooling resources to ease the administrative burdens of all. Once that arrangement is in place, the group can consider more ambitious projects, such as the joint purchase of an EHR system, sharing of personnel to lower staffing costs, and an integrated scheduling system. The latter will be particularly attractive to participants in later stages of their careers who are considering an intermediate option, somewhere between full-time work and complete retirement.

After a time, when the structure is stabilized and everyone agrees that his or her individual and shared interests and goals are being met, an outright merger can be contemplated. Projects of this scope require careful planning and implementation, and should not be undertaken without the help of competent legal counsel and an experienced business consultant.

A more complex but increasingly popular option is to join other small practices and providers in an independent practice association (IPA). An IPA is a legal entity organized and directed by physicians for the purpose of negotiating contracts with insurance companies on their behalf. Because of its structure, an IPA is better positioned to enter into such financial arrangements, and to counterbalance the leverage of insurers, but there are legal issues to consider. Many IPAs are vulnerable to antitrust charges because they include competing health care providers. You should check with legal counsel before signing on to an IPA, to make sure that it abides by antitrust and price fixing laws. IPAs have also been known to fail, particularly in states where they are not adequately regulated.

A possible successor to IPAs is the accountable care organization (ACO), an entity born as a component of the Affordable Care Act. While the official definition remains nebulous, an ACO is basically a network of doctors and hospitals that shares financial and medical responsibility for providing coordinated and efficient care to patients. The goal of ACO participants is to limit unnecessary spending, both individually and collectively, according to criteria established by the Centers for Medicare & Medicaid Services, without compromising quality of care in the process. More than 600 ACOs had been approved by the CMS as of the beginning of 2014.

It is important to remember that the ACO model remains very much a work in progress. ACOs make providers jointly accountable for the health of their patients. They offer financial incentives to cooperate, and to save money by avoiding unnecessary tests and procedures. A key component is the sharing of information. Providers who save money while also meeting quality targets are theoretically entitled to a portion of the savings.

As with IPAs, ACO ventures involve a measure of risk. ACOs that fail to meet the CMS performance and savings benchmarks can be stuck with the bill for investments made to improve care, such as equipment and computer purchases and the hiring of mid-level providers and managers, and they may be assessed monetary penalties as well. ACOs sponsored by physicians or rural providers, however, can apply to receive payments in advance to help finance infrastructure investments – a concession the Obama administration made after receiving complaints from rural hospitals.

Clearly, the price of remaining autonomous will be significant, and many private practitioners will be unwilling to pay it: Only 36% of physicians remained in independent practice at the end of the 2013, according to data from the American Medical Association – down from 57% in 2000 – but those of us who remain committed to independence will find ways to preserve it. In medicine, as in life, those most responsive to change will survive and flourish.

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News.

SAN DIEGO – Cutaneous squamous cell carcinomas from organ transplant recipients had a more aggressive molecular profile than did tumor samples from immunocompetent patients, according to an RNA sequencing study presented at the annual meeting of the American Society for Dermatologic Surgery.

Specimens from organ transplant recipients showed greater induction of biologic pathways related to cancer signaling, fibrosis, and extracellular matrix remodeling, said Dr. Cameron Chesnut, a dermatologist in private practice in Spokane, Wash., who carried out the research while he was a dermatologic surgery resident at the University of California, Los Angeles.

Furthermore, the TP53 tumor suppressor gene was inhibited at least five times more in samples from organ transplant recipients, compared with those from immunocompetent patients, Dr. Chesnut said in an interview.

Squamous cell carcinoma (SCC) is the most common cancer to occur after organ transplantation, Dr. Chesnut and his associates noted. The malignancy is 65-250 times more common, is more than 4 times more likely to metastasize, and has a mortality rate of 5% compared with a rate of less than 1% in immunocompetent patients, based on data published online in the journal F1000 Prime Reports, they said.

To characterize these high-risk SCCs and compare them with lower-risk SCCs, the researchers performed RNA sequencing of three normal skin samples and SCC specimens from 15 patients – 7 organ transplant recipients and 8 otherwise healthy individuals. The researchers used an Illumina GAIIx RNA Seq instrument to generate RNA sequencing libraries of the specimens. They also used the web-based Ingenuity Pathway Analysis technique to identify the major biological pathways regulated within the tumors.

In all, 690 highly expressed genes were induced at least fivefold in SCCs from organ transplant recipients compared with those from otherwise healthy patients. These genes encoded pathways related to fibrosis, extracellular remodeling, the cell cycle, and tumor signaling, the investigators said. The COX-2 pathway for prostaglandin synthesis also was induced fivefold or more in the high-risk SCCs compared with those from immunocompetent patients, Dr. Chesnut added.

The researchers also identified 1,290 highly expressed genes that were inhibited at least fivefold in SCCs from organ transplant recipients compared with specimens from immunocompetent patients. The most strongly inhibited pathways were related to sterol biosynthesis and epithelial differentiation, followed by nucleotide excision repair, interleukin-6 and IL-17, and apoptosis, they said.

Based on these findings, novel therapeutics might someday be able to target specific biologic pathways that are highly induced in SCCs from organ transplant recipients, Dr. Chesnut said. “It’s hard to say what the most likely candidates are,” but based on the study findings, “regulating inflammation may be a target,” he added. Dr. Chesnut and his associates reported no external funding sources or conflicts of interest.

SAN DIEGO – Cutaneous squamous cell carcinomas from organ transplant recipients had a more aggressive molecular profile than did tumor samples from immunocompetent patients, according to an RNA sequencing study presented at the annual meeting of the American Society for Dermatologic Surgery.

Specimens from organ transplant recipients showed greater induction of biologic pathways related to cancer signaling, fibrosis, and extracellular matrix remodeling, said Dr. Cameron Chesnut, a dermatologist in private practice in Spokane, Wash., who carried out the research while he was a dermatologic surgery resident at the University of California, Los Angeles.

Furthermore, the TP53 tumor suppressor gene was inhibited at least five times more in samples from organ transplant recipients, compared with those from immunocompetent patients, Dr. Chesnut said in an interview.

Squamous cell carcinoma (SCC) is the most common cancer to occur after organ transplantation, Dr. Chesnut and his associates noted. The malignancy is 65-250 times more common, is more than 4 times more likely to metastasize, and has a mortality rate of 5% compared with a rate of less than 1% in immunocompetent patients, based on data published online in the journal F1000 Prime Reports, they said.

To characterize these high-risk SCCs and compare them with lower-risk SCCs, the researchers performed RNA sequencing of three normal skin samples and SCC specimens from 15 patients – 7 organ transplant recipients and 8 otherwise healthy individuals. The researchers used an Illumina GAIIx RNA Seq instrument to generate RNA sequencing libraries of the specimens. They also used the web-based Ingenuity Pathway Analysis technique to identify the major biological pathways regulated within the tumors.

In all, 690 highly expressed genes were induced at least fivefold in SCCs from organ transplant recipients compared with those from otherwise healthy patients. These genes encoded pathways related to fibrosis, extracellular remodeling, the cell cycle, and tumor signaling, the investigators said. The COX-2 pathway for prostaglandin synthesis also was induced fivefold or more in the high-risk SCCs compared with those from immunocompetent patients, Dr. Chesnut added.

The researchers also identified 1,290 highly expressed genes that were inhibited at least fivefold in SCCs from organ transplant recipients compared with specimens from immunocompetent patients. The most strongly inhibited pathways were related to sterol biosynthesis and epithelial differentiation, followed by nucleotide excision repair, interleukin-6 and IL-17, and apoptosis, they said.

Based on these findings, novel therapeutics might someday be able to target specific biologic pathways that are highly induced in SCCs from organ transplant recipients, Dr. Chesnut said. “It’s hard to say what the most likely candidates are,” but based on the study findings, “regulating inflammation may be a target,” he added. Dr. Chesnut and his associates reported no external funding sources or conflicts of interest.

SAN DIEGO – Cutaneous squamous cell carcinomas from organ transplant recipients had a more aggressive molecular profile than did tumor samples from immunocompetent patients, according to an RNA sequencing study presented at the annual meeting of the American Society for Dermatologic Surgery.

Specimens from organ transplant recipients showed greater induction of biologic pathways related to cancer signaling, fibrosis, and extracellular matrix remodeling, said Dr. Cameron Chesnut, a dermatologist in private practice in Spokane, Wash., who carried out the research while he was a dermatologic surgery resident at the University of California, Los Angeles.

Furthermore, the TP53 tumor suppressor gene was inhibited at least five times more in samples from organ transplant recipients, compared with those from immunocompetent patients, Dr. Chesnut said in an interview.

Squamous cell carcinoma (SCC) is the most common cancer to occur after organ transplantation, Dr. Chesnut and his associates noted. The malignancy is 65-250 times more common, is more than 4 times more likely to metastasize, and has a mortality rate of 5% compared with a rate of less than 1% in immunocompetent patients, based on data published online in the journal F1000 Prime Reports, they said.

To characterize these high-risk SCCs and compare them with lower-risk SCCs, the researchers performed RNA sequencing of three normal skin samples and SCC specimens from 15 patients – 7 organ transplant recipients and 8 otherwise healthy individuals. The researchers used an Illumina GAIIx RNA Seq instrument to generate RNA sequencing libraries of the specimens. They also used the web-based Ingenuity Pathway Analysis technique to identify the major biological pathways regulated within the tumors.

In all, 690 highly expressed genes were induced at least fivefold in SCCs from organ transplant recipients compared with those from otherwise healthy patients. These genes encoded pathways related to fibrosis, extracellular remodeling, the cell cycle, and tumor signaling, the investigators said. The COX-2 pathway for prostaglandin synthesis also was induced fivefold or more in the high-risk SCCs compared with those from immunocompetent patients, Dr. Chesnut added.

The researchers also identified 1,290 highly expressed genes that were inhibited at least fivefold in SCCs from organ transplant recipients compared with specimens from immunocompetent patients. The most strongly inhibited pathways were related to sterol biosynthesis and epithelial differentiation, followed by nucleotide excision repair, interleukin-6 and IL-17, and apoptosis, they said.

Based on these findings, novel therapeutics might someday be able to target specific biologic pathways that are highly induced in SCCs from organ transplant recipients, Dr. Chesnut said. “It’s hard to say what the most likely candidates are,” but based on the study findings, “regulating inflammation may be a target,” he added. Dr. Chesnut and his associates reported no external funding sources or conflicts of interest.

Diagnosis: Roseola

Roseola, also known as exanthema subitum or sixth disease, is a common viral infection that affects children by the age of 2 years, most commonly between ages 6 and 15 months. Two strains of viruses, human herpes virus 6 and 7, are the most common causes. Roseola spreads from person to person through respiratory secretions. Symptoms can vary in severity and can start with a sudden high fever, often greater than 103° F, that can last several days and may be associated with a febrile seizure. Associated symptoms may include sore throat, runny nose, cough, and lymphadenopathy.

After the fever resolves, erythematous macules and papules develop, starting on the chest, back, or abdomen and subsequently spreading to the neck and arms. The rash is not typically pruritic, is not contagious, and can last anywhere from several hours to several days. It is important to note that a person with roseola is contagious even if no rash is present. 

Roseola can be difficult to diagnose given the nonspecific symptoms that are very similar to those of other childhood illnesses. Diagnosis is often clinical, based on history and physical, but can be confirmed by the characteristic rash or by detecting antibodies to roseola. 

Treatment of roseola is supportive, with most children recovering within a week. Over-the-counter medications to treat fever, such as acetaminophen and ibuprofen, can be used, but aspirin should be avoided to treat fever in children younger than 2 years given the risk of Reye's syndrome. Antibodies developed against roseola are protective against future infections. Measures should be taken to avoid contact with those infected and hands should be washed frequently to avoid spreading the virus. Adults can contract roseola if they did not have it as a child; the disease is milder in adults but they can spread it to children. 

Another common viral childhood illness is hand, foot, and mouth disease, caused by an enterovirus (coxsackievirus) that leads to sores and blisters on the hands, feet, and buttocks/legs that last for a week. The virus is spread through coughing and sneezing and through fecal-to-oral transmission. Symptoms include sore throat and fever with the rash. Diagnosis is clinical, based on history and physical exam, and the condition is treated supportively similar to roseola. 

Another common illness is erythema infectiosum, also known as fifth disease, and is caused by parvovirus B19. The virus is common among school-aged children. The rash typically starts as erythematous patches on the cheeks giving the characteristic "slapped cheek" appearance. By the time the rash appears, the child is no longer contagious. The virus is spread through respiratory secretions.

Adults whose occupations put them in close contact with children can become infected with symptoms, including joint pain, rather than the rash. Infection in pregnant women and patients with sickle cell disease carries an increased risk of miscarriage and severe anemia, respectively. Similar to roseola and hand, foot, and mouth disease, diagnosis of fifth disease is clinical, and treatment is largely supportive. 

Diagnosis: Roseola

Roseola, also known as exanthema subitum or sixth disease, is a common viral infection that affects children by the age of 2 years, most commonly between ages 6 and 15 months. Two strains of viruses, human herpes virus 6 and 7, are the most common causes. Roseola spreads from person to person through respiratory secretions. Symptoms can vary in severity and can start with a sudden high fever, often greater than 103° F, that can last several days and may be associated with a febrile seizure. Associated symptoms may include sore throat, runny nose, cough, and lymphadenopathy.

After the fever resolves, erythematous macules and papules develop, starting on the chest, back, or abdomen and subsequently spreading to the neck and arms. The rash is not typically pruritic, is not contagious, and can last anywhere from several hours to several days. It is important to note that a person with roseola is contagious even if no rash is present. 

Roseola can be difficult to diagnose given the nonspecific symptoms that are very similar to those of other childhood illnesses. Diagnosis is often clinical, based on history and physical, but can be confirmed by the characteristic rash or by detecting antibodies to roseola. 

Treatment of roseola is supportive, with most children recovering within a week. Over-the-counter medications to treat fever, such as acetaminophen and ibuprofen, can be used, but aspirin should be avoided to treat fever in children younger than 2 years given the risk of Reye's syndrome. Antibodies developed against roseola are protective against future infections. Measures should be taken to avoid contact with those infected and hands should be washed frequently to avoid spreading the virus. Adults can contract roseola if they did not have it as a child; the disease is milder in adults but they can spread it to children. 

Another common viral childhood illness is hand, foot, and mouth disease, caused by an enterovirus (coxsackievirus) that leads to sores and blisters on the hands, feet, and buttocks/legs that last for a week. The virus is spread through coughing and sneezing and through fecal-to-oral transmission. Symptoms include sore throat and fever with the rash. Diagnosis is clinical, based on history and physical exam, and the condition is treated supportively similar to roseola. 

Another common illness is erythema infectiosum, also known as fifth disease, and is caused by parvovirus B19. The virus is common among school-aged children. The rash typically starts as erythematous patches on the cheeks giving the characteristic "slapped cheek" appearance. By the time the rash appears, the child is no longer contagious. The virus is spread through respiratory secretions.

Adults whose occupations put them in close contact with children can become infected with symptoms, including joint pain, rather than the rash. Infection in pregnant women and patients with sickle cell disease carries an increased risk of miscarriage and severe anemia, respectively. Similar to roseola and hand, foot, and mouth disease, diagnosis of fifth disease is clinical, and treatment is largely supportive. 

Diagnosis: Roseola

Roseola, also known as exanthema subitum or sixth disease, is a common viral infection that affects children by the age of 2 years, most commonly between ages 6 and 15 months. Two strains of viruses, human herpes virus 6 and 7, are the most common causes. Roseola spreads from person to person through respiratory secretions. Symptoms can vary in severity and can start with a sudden high fever, often greater than 103° F, that can last several days and may be associated with a febrile seizure. Associated symptoms may include sore throat, runny nose, cough, and lymphadenopathy.

After the fever resolves, erythematous macules and papules develop, starting on the chest, back, or abdomen and subsequently spreading to the neck and arms. The rash is not typically pruritic, is not contagious, and can last anywhere from several hours to several days. It is important to note that a person with roseola is contagious even if no rash is present. 

Roseola can be difficult to diagnose given the nonspecific symptoms that are very similar to those of other childhood illnesses. Diagnosis is often clinical, based on history and physical, but can be confirmed by the characteristic rash or by detecting antibodies to roseola. 

Treatment of roseola is supportive, with most children recovering within a week. Over-the-counter medications to treat fever, such as acetaminophen and ibuprofen, can be used, but aspirin should be avoided to treat fever in children younger than 2 years given the risk of Reye's syndrome. Antibodies developed against roseola are protective against future infections. Measures should be taken to avoid contact with those infected and hands should be washed frequently to avoid spreading the virus. Adults can contract roseola if they did not have it as a child; the disease is milder in adults but they can spread it to children. 

Another common viral childhood illness is hand, foot, and mouth disease, caused by an enterovirus (coxsackievirus) that leads to sores and blisters on the hands, feet, and buttocks/legs that last for a week. The virus is spread through coughing and sneezing and through fecal-to-oral transmission. Symptoms include sore throat and fever with the rash. Diagnosis is clinical, based on history and physical exam, and the condition is treated supportively similar to roseola. 

Another common illness is erythema infectiosum, also known as fifth disease, and is caused by parvovirus B19. The virus is common among school-aged children. The rash typically starts as erythematous patches on the cheeks giving the characteristic "slapped cheek" appearance. By the time the rash appears, the child is no longer contagious. The virus is spread through respiratory secretions.

Adults whose occupations put them in close contact with children can become infected with symptoms, including joint pain, rather than the rash. Infection in pregnant women and patients with sickle cell disease carries an increased risk of miscarriage and severe anemia, respectively. Similar to roseola and hand, foot, and mouth disease, diagnosis of fifth disease is clinical, and treatment is largely supportive.